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Merrill SM, Konwar C, Fraihat Z, Parent J, Dajani R. Molecular insights into trauma: A framework of epigenetic pathways to resilience through intervention. MED 2025; 6:100560. [PMID: 39708797 DOI: 10.1016/j.medj.2024.11.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 10/01/2024] [Accepted: 11/25/2024] [Indexed: 12/23/2024]
Abstract
Experiences of complex trauma and adversity, especially for children, are ongoing global crises necessitating adaptation. Bioadaptability to adversity and its health consequences emphasizes the dynamism of adaptation to trauma and the potential for research to inform intervention strategies. Epigenetic variability, particularly DNA methylation, associates with chronic adversity while allowing for resilience and adaptability. Epigenetics, including age- and site-specific changes in DNA methylation, gene-environment interactions, pharmacological responses, and biomarker characterization and evaluation, may aid in understanding trauma responses and promoting well-being by facilitating psychological and biological adaptation. Understanding these molecular processes provides a foundation for a biologically adaptive framework to shift public health strategies from restorative to long-term adaptation and resilience. Psychological, cultural, and biological trauma must be addressed in innovative interventions for vulnerable populations, particularly children and adolescents. Understanding molecular changes may provide a biopsychosocial perspective for culturally sensitive, evidence-based interventions that promote resilience and thriving in new settings.
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Affiliation(s)
- Sarah M Merrill
- Department of Psychology, University of Massachusetts Lowell, Lowell, MA, USA.
| | - Chaini Konwar
- BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada
| | - Zaid Fraihat
- School of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Justin Parent
- Department of Psychology, University of Massachusetts Lowell, Lowell, MA, USA; Department of Psychology, College of Health Sciences, University of Rhode Island, Kingston, RI, USA; Emma Pendleton Bradley Hospital, East Providence, RI, USA
| | - Rana Dajani
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan.
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2
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D'Addario C, Di Bartolomeo M. Epigenetic Control in Schizophrenia. Subcell Biochem 2025; 108:191-215. [PMID: 39820863 DOI: 10.1007/978-3-031-75980-2_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
Schizophrenia is a severe and complex psychiatric condition ranking among the top 15 leading causes of disability worldwide. Despite the well-established heritability component, a complex interplay between genetic and environmental risk factors plays a key role in the development of schizophrenia and psychotic disorders in general. This chapter covers all the clinical evidence showing how the analysis of the epigenetic modulation in schizophrenia might be relevant to understand the pathogenesis of schizophrenia as well as potentially useful to develop new pharmacotherapies.
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Affiliation(s)
- Claudio D'Addario
- Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.
| | - Martina Di Bartolomeo
- Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
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3
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Fungaro Rissatti L, Wilson D, Palace-Berl F, de Mello Ponteciano B, Sardela de Miranda F, Alece Arantes Moreno I, dos Santos Vieira T, Pereira Sorroche B, Rebolho Batista Arantes LM, Madeira Alvares da Silva A, D'Almeida V, Demarzo M, Rodrigues de Oliveira D. BDNF methylation associated with stress in women: Novel insights in epigenetics and inflammation. Brain Behav Immun Health 2024; 42:100900. [PMID: 39552782 PMCID: PMC11565430 DOI: 10.1016/j.bbih.2024.100900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 09/16/2024] [Accepted: 10/27/2024] [Indexed: 11/19/2024] Open
Abstract
The brain-derived neurotrophic factor (BDNF) gene plays an important role in modulating the stress-response axis and inflammation, which can be regulated by epigenetic mechanisms. BNDF methylation has been associated with stress-related psychiatric disorders such as depression, anxiety and post-traumatic stress. Previous studies have reported that stressful events are involved with long-lasting alterations in DNA methylation (DNAm) of the BNDF exon IV promoter, suggesting that glucocorticoids and inflammatory cytokines can regulate this process. We previously found that perceived psychological stress is modulated by inflammatory cytokines, such as interleukin (IL)-6, IL-8 and IL-10, and IL-12p70, suggesting their role in mediating the stress response. However, the epigenetic mechanism mediating this response has yet to be fully understood. In this study, we propose that high perceived stress and high serum levels of inflammatory cytokines may correlate with specific methylation sites within the BNDF exon IV promoter. To address these questions, we conducted a cross-sectional study of 82 adult women teachers working in basic education in Brazil. The perceived stress scale was used to assess stress and blood samples were collected for the measurement of inflammatory markers and BNDF methylation through flow cytometry assay and DNA pyrosequencing, respectively. We detected differentially methylated CpG sites in the BNDF gene, where 5 CpG sites were directly correlated with high stress levels. However, 4 CpG sites showed inverse effects, indicating that changes in methylation levels in those sites could lead to a protective effect on perceived stress. About inflammatory markers, IL-6 and IL-8 were associated with high perceived stress. However, only IL-8 and IL-10 showed simultaneous modulation of perceived stress, while IL-10 and IL12p70 correlated with DNAm. We found that higher levels in IL-10 and IL-12p70 serum decrease methylation in CpG11. A direct relationship was also found to IL-12p70, where higher levels in serum increase methylation in CpG5 and 13, respectively. Taken as a whole, our findings reinforce the hypothesis regarding stress-sensitive regions within the BDNF gene, mainly for CpG5, 11, and 13. In addition to these results, CpG7 and 9 may be regarded as stress-protective regions. Our data suggest that BDNF DNAm in the blood may represent a novel biomarker for early detection of adverse effects of chronic exposure to stress in healthy individuals.
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Affiliation(s)
- Luciana Fungaro Rissatti
- Department of Pathology, Graduate Program in Pathology, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - David Wilson
- Department of Preventive Medicine, Graduate Program in Collective Health, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Fanny Palace-Berl
- Department of Pathology, Graduate Program in Pathology, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Bárbara de Mello Ponteciano
- Department of Pathology, Graduate Program in Pathology, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Flávia Sardela de Miranda
- Laboratory of Imunomodulation, Department of Imunology, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Ivana Alece Arantes Moreno
- Biotechnology/Renorbio Postgraduate Program, Universidade Federal do Espírito Santo, Vitória, ES, Brazil
| | - Tamires dos Santos Vieira
- Biotechnology/Renorbio Postgraduate Program, Universidade Federal do Espírito Santo, Vitória, ES, Brazil
| | - Bruna Pereira Sorroche
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | | | | | - Vânia D'Almeida
- Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Marcelo Demarzo
- Department of Preventive Medicine, Graduate Program in Collective Health, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Mente Aberta - Brazilian Center for Mindfulness and Health Promotion, Departamento de Medicina Preventiva, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Daniela Rodrigues de Oliveira
- Department of Pathology, Graduate Program in Pathology, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Department of Preventive Medicine, Graduate Program in Collective Health, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Mente Aberta - Brazilian Center for Mindfulness and Health Promotion, Departamento de Medicina Preventiva, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
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Li Z, Kong W, Park HY, Koo SJ, Bang M, Park JT, Lee E, An SK. Association of hair cortisol concentration with brain-derived neurotrophic factor gene methylation: The role of sex as a moderator. Stress Health 2024; 40:e3401. [PMID: 38581566 DOI: 10.1002/smi.3401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 03/20/2024] [Accepted: 03/29/2024] [Indexed: 04/08/2024]
Abstract
Hair cortisol concentration (HCC) reflects the long-term activity of the hypothalamus-pituitary-adrenal (HPA) axis in response to stress. Brain-derived neurotrophic factor DNA methylation (BDNF DNAM) may affect HCC, and sex and Val66Met may contribute to this association. Thus, the aim of this study was to investigate the associations between HCC and Brain-derived neurotrophic factor (BDNF) DNAM, and the moderating effects of Val66Met and sex. We recruited 191 healthy young participants (96 women, mean age 23.0 ± 2.6 years) and collected body samples to evaluate HCC, and to determine BDNF DNAM and Val66Met genotypes. We analyzed the effects of BDNF DNAM, sex, and Val66Met on HCC. We also evaluated the associations between BDNF DNAM and HCC in groups separated by sex and genotypes. We found a marked association of BDNF DNAM with HCC across men and women. After dividing the data by sex, a positive correlation of HCC with BDNF DNAM was found only in women. There was no substantial moderation effect of Val66Met genotypes on the association between BDNF DNAM and HCC. Therefore, BDNF DNAM was found to have positive association with HCC only in healthy young women, indicating that sex moderates the association of BDNF DNAM with long-term HPA axis activity.
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Affiliation(s)
- Zhenxu Li
- Section of Self, Affect and Neuroscience, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei University College of Medicine, Seoul, South Korea
| | - Wanji Kong
- Section of Self, Affect and Neuroscience, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei University College of Medicine, Seoul, South Korea
| | - Hye Yoon Park
- Section of Self, Affect and Neuroscience, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Se Jun Koo
- Section of Self, Affect and Neuroscience, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Graduate Program in Cognitive Science, Yonsei University, Seoul, South Korea
| | - Minji Bang
- Department of Psychiatry, CHA University School of Medicine, Seongnam-si, Gyeonggi-do, South Korea
| | - Jung Tak Park
- Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, South Korea
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Eun Lee
- Section of Self, Affect and Neuroscience, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Department of Psychiatry, Yonsei University College of Medicine, Severance Hospital, Seoul, South Korea
| | - Suk Kyoon An
- Section of Self, Affect and Neuroscience, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Graduate Program in Cognitive Science, Yonsei University, Seoul, South Korea
- Department of Psychiatry, Yonsei University College of Medicine, Severance Hospital, Seoul, South Korea
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5
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Huang H, Xie B, Liu Y, Dong GH, Liu R, Gui Z, Chen L, Li S, Guo Y, Yang L, Chen G. Long-term exposure to PM 2.5 compositions and O 3 and their interactive effects on DNA methylation of peripheral brain-derived neurotrophic factor promoter. INTERNATIONAL JOURNAL OF ENVIRONMENTAL HEALTH RESEARCH 2024; 34:2957-2968. [PMID: 37939783 DOI: 10.1080/09603123.2023.2280157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 11/01/2023] [Indexed: 11/10/2023]
Abstract
This study examined the associations of long-term exposure to ambient fine particulate matter (PM2.5) compositions/ozone with methylation of peripheral brain-derived neurotrophic factor (BDNF) promoters. A total of 101 participants were recruited from a cohort in Shijiazhuang, Hebei province, China. They underwent baseline and follow-up surveys in 2011 and 2015. DNA methylation levels were detected by bisulfite-PCR amplification and pyrosequencing. Participants' three-year average levels of PM2.5 compositions and ozone were estimated. Bayesian kernel machine regression (BKMR) models were used to examine the joint effects of pollutants on methylation levels. Exposure to PM2.5 compositions and ozone mixtures at the 75th percentile was associated with increased methylation levels at CpG2 of BDNF promoter (203%, 95% CI: 89, 316) than the lowest level of exposure, and sulfate dominated the effect in the BKMR models.Our findings provide clues to the epigenetic mechanisms for the associations of PM2.5 compositions and ozone with BDNF.
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Affiliation(s)
- Haoyu Huang
- Department of Occupational and Environmental Health, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Bing Xie
- College of Forensic Medicine, Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, China
| | - Yuewei Liu
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Guang-Hui Dong
- Department of Occupational and Environmental Health, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Ruqing Liu
- Department of Occupational and Environmental Health, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Zhaohuan Gui
- Department of Occupational and Environmental Health, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Lijun Chen
- College of Information Engineering, Hubei University of Chinese Medicine, Wuhan, China
| | - Shanshan Li
- Climate, Air Quality Research Unit, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Yuming Guo
- Climate, Air Quality Research Unit, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Lei Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Shijiazhuang, China
| | - Gongbo Chen
- Climate, Air Quality Research Unit, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
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Karaglani M, Agorastos A, Panagopoulou M, Parlapani E, Athanasis P, Bitsios P, Tzitzikou K, Theodosiou T, Iliopoulos I, Bozikas VP, Chatzaki E. A novel blood-based epigenetic biosignature in first-episode schizophrenia patients through automated machine learning. Transl Psychiatry 2024; 14:257. [PMID: 38886359 PMCID: PMC11183091 DOI: 10.1038/s41398-024-02946-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 05/15/2024] [Accepted: 05/17/2024] [Indexed: 06/20/2024] Open
Abstract
Schizophrenia (SCZ) is a chronic, severe, and complex psychiatric disorder that affects all aspects of personal functioning. While SCZ has a very strong biological component, there are still no objective diagnostic tests. Lately, special attention has been given to epigenetic biomarkers in SCZ. In this study, we introduce a three-step, automated machine learning (AutoML)-based, data-driven, biomarker discovery pipeline approach, using genome-wide DNA methylation datasets and laboratory validation, to deliver a highly performing, blood-based epigenetic biosignature of diagnostic clinical value in SCZ. Publicly available blood methylomes from SCZ patients and healthy individuals were analyzed via AutoML, to identify SCZ-specific biomarkers. The methylation of the identified genes was then analyzed by targeted qMSP assays in blood gDNA of 30 first-episode drug-naïve SCZ patients and 30 healthy controls (CTRL). Finally, AutoML was used to produce an optimized disease-specific biosignature based on patient methylation data combined with demographics. AutoML identified a SCZ-specific set of novel gene methylation biomarkers including IGF2BP1, CENPI, and PSME4. Functional analysis investigated correlations with SCZ pathology. Methylation levels of IGF2BP1 and PSME4, but not CENPI were found to differ, IGF2BP1 being higher and PSME4 lower in the SCZ group as compared to the CTRL group. Additional AutoML classification analysis of our experimental patient data led to a five-feature biosignature including all three genes, as well as age and sex, that discriminated SCZ patients from healthy individuals [AUC 0.755 (0.636, 0.862) and average precision 0.758 (0.690, 0.825)]. In conclusion, this three-step pipeline enabled the discovery of three novel genes and an epigenetic biosignature bearing potential value as promising SCZ blood-based diagnostics.
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Affiliation(s)
- Makrina Karaglani
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, GR-68132, Alexandroupolis, Greece
- Institute of Agri-food and Life Sciences, University Research & Innovation Center, H.M.U.R.I.C., Hellenic Mediterranean University, GR-71003, Crete, Greece
| | - Agorastos Agorastos
- Institute of Agri-food and Life Sciences, University Research & Innovation Center, H.M.U.R.I.C., Hellenic Mediterranean University, GR-71003, Crete, Greece
- II. Department of Psychiatry, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, GR-56430, Thessaloniki, Greece
| | - Maria Panagopoulou
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, GR-68132, Alexandroupolis, Greece
- Institute of Agri-food and Life Sciences, University Research & Innovation Center, H.M.U.R.I.C., Hellenic Mediterranean University, GR-71003, Crete, Greece
| | - Eleni Parlapani
- Ι. Department of Psychiatry, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, GR-56429, Thessaloniki, Greece
| | - Panagiotis Athanasis
- II. Department of Psychiatry, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, GR-56430, Thessaloniki, Greece
| | - Panagiotis Bitsios
- Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, GR-71500, Heraklion, Greece
| | - Konstantina Tzitzikou
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, GR-68132, Alexandroupolis, Greece
| | - Theodosis Theodosiou
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, GR-68132, Alexandroupolis, Greece
- ABCureD P.C, GR-68131, Alexandroupolis, Greece
| | - Ioannis Iliopoulos
- Division of Basic Sciences, School of Medicine, University of Crete, GR-71003, Heraklion, Greece
| | - Vasilios-Panteleimon Bozikas
- II. Department of Psychiatry, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, GR-56430, Thessaloniki, Greece
| | - Ekaterini Chatzaki
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, GR-68132, Alexandroupolis, Greece.
- Institute of Agri-food and Life Sciences, University Research & Innovation Center, H.M.U.R.I.C., Hellenic Mediterranean University, GR-71003, Crete, Greece.
- ABCureD P.C, GR-68131, Alexandroupolis, Greece.
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 70013, Heraklion, Greece.
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7
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Huang M, Tao X, Bao J, Wang J, Gong X, Luo L, Pan S, Yang R, Gui Y, Zhou H, Xia Y, Yang Y, Sun B, Liu W, Shu X. GADD45B in the ventral hippocampal CA1 modulates aversive memory acquisition and spatial cognition. Life Sci 2024; 346:122618. [PMID: 38614306 DOI: 10.1016/j.lfs.2024.122618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 04/01/2024] [Accepted: 04/05/2024] [Indexed: 04/15/2024]
Abstract
AIMS This study was designed to investigate the role of growth arrest and DNA damage-inducible β (GADD45B) in modulating fear memory acquisition and elucidate its underlying mechanisms. MAIN METHODS Adeno-associated virus (AAV) that knockdown or overexpression GADD45B were injected into ventral hippocampal CA1 (vCA1) by stereotactic, and verified by fluorescence and Western blot. The contextual fear conditioning paradigm was employed to examine the involvement of GADD45B in modulating aversive memory acquisition. The Y-maze and novel location recognition (NLR) tests were used to examine non-aversive cognition. The synaptic plasticity and electrophysiological properties of neurons were measured by slice patch clamp. KEY FINDINGS Knockdown of GADD45B in the vCA1 significantly enhanced fear memory acquisition, accompanied by an upregulation of long-term potentiation (LTP) expression and intrinsic excitability of vCA1 pyramidal neurons (PNs). Conversely, overexpression of GADD45B produced the opposite effects. Notably, silencing the activity of vCA1 neurons abolished the impact of GADD45B knockdown on fear memory development. Moreover, mice with vCA1 GADD45B overexpression exhibited impaired spatial cognition, whereas mice with GADD45B knockdown did not display such impairment. SIGNIFICANCE These results provided compelling evidence for the crucial involvement of GADD45B in the formation of aversive memory and spatial cognition.
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Affiliation(s)
- Mengbing Huang
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Xiaoqing Tao
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Jian Bao
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Ji Wang
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Xiaokang Gong
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Laijie Luo
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Sijie Pan
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Rong Yang
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Yuran Gui
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - HongYan Zhou
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Yiyuan Xia
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Youhua Yang
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Binlian Sun
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Wei Liu
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China.
| | - Xiji Shu
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China.
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8
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Penadés R, Almodóvar-Payá C, García-Rizo C, Ruíz V, Catalán R, Valero S, Wykes T, Fatjó-Vilas M, Arias B. Changes in BDNF methylation patterns after cognitive remediation therapy in schizophrenia: A randomized and controlled trial. J Psychiatr Res 2024; 173:166-174. [PMID: 38537483 DOI: 10.1016/j.jpsychires.2024.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 03/09/2024] [Accepted: 03/13/2024] [Indexed: 04/17/2024]
Abstract
Although cognitive remediation therapy (CRT) produces cognitive benefits in schizophrenia, we do not yet understand whether molecular changes are associated with this cognitive improvement. A gene central to synaptic plasticity, the BDNF, has been proposed as one potential route. This study assesses whether BDNF methylation changes following CRT-produced cognitive improvement are detected. A randomized and controlled trial was performed with two groups (CRT, n = 40; TAU: Treatment as Usual, n = 20) on a sample of participants with schizophrenia. CRT was delivered by trained therapists using a web-based computerized program. Mixed Models, where the interaction of treatment (CRT, TAU) by time (T0: 0 weeks, T1: 16 weeks) was the main effect were used. Then, we tested the association between the treatment and methylation changes in three CpG islands of the BDNF gene. CRT group showed significant improvements in some cognitive domains. Between-groups differential changes in 5 CpG units over time were found, 4 in island 1 (CpG1.2, CpG1.7, CpG1.10, CpG1.17) and 1 in island 3 (CpG3.2). CRT group showed increases in methylation in CpG1.2, CpG1.7 and decreases in pG1.10, CpG1.17, and CpG3.2. Differences in the degree of methylation were associated with changes in Speed of Processing, Working Memory, and Verbal Learning within the CRT group. Those findings provide new data on the relationship between cognitive improvement and changes in peripheral methylation levels of BDNF gene, a key factor involved in neuroplasticity regulation. Trial Registration: NCT04278027.
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Affiliation(s)
- Rafael Penadés
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic, Barcelona, Spain; Clinical Psychology and Psychobiology, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.
| | - Carmen Almodóvar-Payá
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain; Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
| | - Clemente García-Rizo
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic, Barcelona, Spain; Clinical Psychology and Psychobiology, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain
| | - Victoria Ruíz
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic, Barcelona, Spain
| | - Rosa Catalán
- Barcelona Clinic Schizophrenia Unit, Hospital Clinic, Barcelona, Spain; Clinical Psychology and Psychobiology, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain
| | - Sergi Valero
- ACE Alzheimer Center Barcelona, Barcelona, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Til Wykes
- Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; South London & Maudsley NHS Foundation Trust, London Hospital, London, United Kingdom
| | - Mar Fatjó-Vilas
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain; Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
| | - Bárbara Arias
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
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9
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Izuo N, Miyanishi H, Nishizawa D, Fujii T, Hasegawa J, Sato N, Tanioka F, Sugimura H, Ikeda K, Nitta A. DNA methylation status of SHATI/NAT8L promoter in the blood of cigarette smokers. Neuropsychopharmacol Rep 2023; 43:570-575. [PMID: 37668111 PMCID: PMC10739067 DOI: 10.1002/npr2.12373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/15/2023] [Accepted: 07/23/2023] [Indexed: 09/06/2023] Open
Abstract
AIMS Cigarette smoking is a preventable risk factor for various diseases such as cancer, ischemic stroke, cardiac stroke, and chronic obstructive pulmonary disease. Smoking cessation is of great importance not only for individual smokers but also for social health. Regarding current cessation therapies, the effectiveness of nicotine replacement is limited, and the cost of varenicline medication is considerable. Thus, a method for screening smokers who are responsive to cessation therapy based on the therapeutic effectiveness is required. Peripheral biomarkers reflecting smoking dependence status are necessary to establish a method for achieving effective cessation therapy. METHODS Methylation status of smokers' blood DNA was evaluated focusing on SHATI/NAT8L, an addiction-related gene. Eight CpG sites in SHATI/NAT8L were quantified by pyrosequencing. RESULTS There was no difference in the methylation status of this gene between smokers (n = 129) and non-smokers (n = 129) at all CpG sites. No correlations between the methylation status of SHATI/NAT8L and indicators of smoking dependence were found. CONCLUSIONS Although the present study found no significance in the DNA methylation of SHATI/NAT8L among smokers, the exploration of predictable peripheral biomarkers for the effectiveness of smoking cessation therapy is required.
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Affiliation(s)
- Naotaka Izuo
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
| | - Hajime Miyanishi
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
| | - Daisuke Nishizawa
- Addictive Substance ProjectTokyo Metropolitan Institute of Medical ScienceTokyoJapan
| | - Takuma Fujii
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
| | - Junko Hasegawa
- Addictive Substance ProjectTokyo Metropolitan Institute of Medical ScienceTokyoJapan
| | - Naomi Sato
- Department of Clinical NursingHamamatsu University School of MedicineShizuokaJapan
- Department of Tumor PathologyHamamatsu University School of MedicineShizuokaJapan
| | - Fumihiko Tanioka
- Department of PathologyIwata City HospitalShizuokaJapan
- Present address:
KDP Pathology Clinic2‐30‐14 Hirosawa Nakaku HamamatsuShizuokaJapan
| | - Haruhiko Sugimura
- Department of Tumor PathologyHamamatsu University School of MedicineShizuokaJapan
- Present address:
Sasaki Institute, Sasaki Foundation2‐2 Kandasurugadai, Chiyoda‐KuTokyo101‐0062Japan
| | - Kazutaka Ikeda
- Addictive Substance ProjectTokyo Metropolitan Institute of Medical ScienceTokyoJapan
| | - Atsumi Nitta
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
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10
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Shaikh A, Li YQ, Lu J. Perspectives on pain in Down syndrome. Med Res Rev 2023; 43:1411-1437. [PMID: 36924439 DOI: 10.1002/med.21954] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 01/08/2023] [Accepted: 02/28/2023] [Indexed: 03/18/2023]
Abstract
Down syndrome (DS) or trisomy 21 is a genetic condition often accompanied by chronic pain caused by congenital abnormalities and/or conditions, such as osteoarthritis, recurrent infections, and leukemia. Although DS patients are more susceptible to chronic pain as compared to the general population, the pain experience in these individuals may vary, attributed to the heterogenous structural and functional differences in the central nervous system, which might result in abnormal pain sensory information transduction, transmission, modulation, and perception. We tried to elaborate on some key questions and possible explanations in this review. Further clarification of the mechanisms underlying such abnormal conditions induced by the structural and functional differences is needed to help pain management in DS patients.
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Affiliation(s)
- Ammara Shaikh
- Department of Human Anatomy, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning Province, China
| | - Yun-Qing Li
- Department of Anatomy, Histology, and Embryology & K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, Shaanxi Province, China
- Department of Anatomy, Basic Medical College, Zhengzhou University, Zhengzhou, China
| | - Jie Lu
- Department of Human Anatomy, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning Province, China
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11
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Treble-Barna A, Heinsberg LW, Stec Z, Breazeale S, Davis TS, Kesbhat AA, Chattopadhyay A, VonVille HM, Ketchum AM, Yeates KO, Kochanek PM, Weeks DE, Conley YP. Brain-derived neurotrophic factor (BDNF) epigenomic modifications and brain-related phenotypes in humans: A systematic review. Neurosci Biobehav Rev 2023; 147:105078. [PMID: 36764636 PMCID: PMC10164361 DOI: 10.1016/j.neubiorev.2023.105078] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 01/17/2023] [Accepted: 02/04/2023] [Indexed: 02/11/2023]
Abstract
Epigenomic modifications of the brain-derived neurotrophic factor (BDNF) gene have been postulated to underlie the pathogenesis of neurodevelopmental, psychiatric, and neurological conditions. This systematic review summarizes current evidence investigating the association of BDNF epigenomic modifications (DNA methylation, non-coding RNA, histone modifications) with brain-related phenotypes in humans. A novel contribution is our creation of an open access web-based application, the BDNF DNA Methylation Map, to interactively visualize specific positions of CpG sites investigated across all studies for which relevant data were available. Our literature search of four databases through September 27, 2021 returned 1701 articles, of which 153 met inclusion criteria. Our review revealed exceptional heterogeneity in methodological approaches, hindering the identification of clear patterns of robust and/or replicated results. We summarize key findings and provide recommendations for future epigenomic research. The existing literature appears to remain in its infancy and requires additional rigorous research to fulfill its potential to explain BDNF-linked risk for brain-related conditions and improve our understanding of the molecular mechanisms underlying their pathogenesis.
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Affiliation(s)
- Amery Treble-Barna
- Department of Physical Medicine & Rehabilitation, School of Medicine, University of Pittsburgh, PA 15261, USA.
| | - Lacey W Heinsberg
- Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Zachary Stec
- Department of Physical Medicine & Rehabilitation, School of Medicine, University of Pittsburgh, PA 15261, USA.
| | - Stephen Breazeale
- Department of Health and Human Development, School of Nursing, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Tara S Davis
- Department of Health Promotion and Development, School of Nursing, University of Pittsburgh, PA 15261, USA.
| | | | - Ansuman Chattopadhyay
- Molecular Biology Information Service, Health Sciences Library System, University of Pittsburgh, USA
| | - Helena M VonVille
- Health Sciences Library System, University of Pittsburgh, PA 15261, USA.
| | - Andrea M Ketchum
- Emeritus Health Sciences Library System, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Keith Owen Yeates
- Department of Psychology, Alberta Children's Hospital Research Institute and Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N1N4, Canada.
| | - Patrick M Kochanek
- Safar Center for Resuscitation Research, Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, PA 15261, USA.
| | - Daniel E Weeks
- Department of Human Genetics and Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Yvette P Conley
- Department of Human Genetics, School of Nursing, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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12
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Zhou A, Ancelin ML, Ritchie K, Ryan J. Childhood adverse events and BDNF promoter methylation in later-life. Front Psychiatry 2023; 14:1108485. [PMID: 36911114 PMCID: PMC9998928 DOI: 10.3389/fpsyt.2023.1108485] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 02/13/2023] [Indexed: 03/14/2023] Open
Abstract
Studies have shown that the effects of early-life stress and trauma can be enduring, with long-term negative effects on health. Epigenetics, including DNA methylation, have been implicated as a potential mechanism for these effects. Brain-derived neurotropic factor (BDNF) is a neurotransmitter involved in learning and memory, and altered BDNF promoter methylation measured in peripheral tissue has been found with early-life stress. However, whether such methylation differences remain stable into later life, is unknown. This study aimed to investigate the association between childhood adversity and BDNF promoter methylation in adults aged 65 years and over. Data came from a large study of older community-dwelling individuals in France (ESPRIT). Information on three major childhood adverse events, namely abuse/maltreatment, war/natural disaster, and financial difficulties/poverty, was obtained by retrospective reporting from participants of ESPRIT study. BDNF promoter I and IV methylation was assessed in blood and buccal tissue. Linear regression analysis was performed, adjusting for age, sex, education, depression, and morbidity. Among 927 participants, there was no strong evidence that childhood abuse/maltreatment or financial difficulties/poverty were associated with BDNF methylation in older individuals. For war/natural disaster, differential methylation at four of twenty-nine CpG sites was observed, however, these would not have remained significant after correction for multiple testing. Together, these findings do not support a long-term association between adverse childhood events and BDNF methylation in older age, but further large prospective studies are needed, which do not target specific genes, but consider DNA methylation across the genome.
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Affiliation(s)
- Aoshuang Zhou
- Division of Epidemiology, Jockey Club School of Public Health and Primary Care, Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Marie-Laure Ancelin
- Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, Montpellier, France
| | - Karen Ritchie
- Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, Montpellier, France
| | - Joanne Ryan
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
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13
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Micale V, Di Bartolomeo M, Di Martino S, Stark T, Dell'Osso B, Drago F, D'Addario C. Are the epigenetic changes predictive of therapeutic efficacy for psychiatric disorders? A translational approach towards novel drug targets. Pharmacol Ther 2023; 241:108279. [PMID: 36103902 DOI: 10.1016/j.pharmthera.2022.108279] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 09/01/2022] [Accepted: 09/01/2022] [Indexed: 02/06/2023]
Abstract
The etiopathogenesis of mental disorders is not fully understood and accumulating evidence support that clinical symptomatology cannot be assigned to a single gene mutation, but it involves several genetic factors. More specifically, a tight association between genes and environmental risk factors, which could be mediated by epigenetic mechanisms, may play a role in the development of mental disorders. Several data suggest that epigenetic modifications such as DNA methylation, post-translational histone modification and interference of microRNA (miRNA) or long non-coding RNA (lncRNA) may modify the severity of the disease and the outcome of the therapy. Indeed, the study of these mechanisms may help to identify patients particularly vulnerable to mental disorders and may have potential utility as biomarkers to facilitate diagnosis and treatment of psychiatric disorders. This article summarizes the most relevant preclinical and human data showing how epigenetic modifications can be central to the therapeutic efficacy of antidepressant and/or antipsychotic agents, as possible predictor of drugs response.
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Affiliation(s)
- Vincenzo Micale
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy.
| | - Martina Di Bartolomeo
- Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Serena Di Martino
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy
| | - Tibor Stark
- Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; Scientific Core Unit Neuroimaging, Max Planck Institute of Psychiatry, Munich, Germany
| | - Bernardo Dell'Osso
- Department of Biomedical and Clinical Sciences 'Luigi Sacco', University of Milan, Milan, Italy, Department of Mental Health, ASST Fatebenefratelli-Sacco, Milan, Italy; "Aldo Ravelli" Research Center for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan Medical School, Milan, Italy; Department of Psychiatry and Behavioral Sciences, Stanford University, CA, USA
| | - Filippo Drago
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy.
| | - Claudio D'Addario
- Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
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14
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Zhang P, Li Y, Wang K, Huang J, Su BB, Xu C, Wang Z, Tan S, Yang F, Tan Y. Altered DNA methylation of CYP2E1 gene in schizophrenia patients with tardive dyskinesia. BMC Med Genomics 2022; 15:253. [PMID: 36494682 PMCID: PMC9733323 DOI: 10.1186/s12920-022-01404-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 11/25/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND About 20-30% of patients with schizophrenia develop tardive dyskinesia (TD). Oxidative stress is one potential causes of TD. CYP2E1 is considered as an oxidative stress-related gene, however, no study has been reported on the DNA methylation levels of the CYP2E1 in schizophrenia or TD. METHODS A total of 35 schizophrenia patients with TD, 35 schizophrenia patients without TD (NTD), and 35 health controls (HCs) were collected in Beijing, China. DNA was extracted from peripheral blood samples. The promoter methylation levels of CYP2E1 were detected using pyrosequencing. The generalized linear model (GLM) was used to examine the methylation levels of three CpG sites among three diagnostic groups (TD vs. NTD vs. HC). RESULTS The average methylation levels were 8.8 ± 10.0, 14.5 ± 11.9 and 15.1 ± 11.3 in TD, NTD and HC groups, respectively. The F-test in GLM revealed overall differences in the average of methylation levels of three CpG sites among three diagnostic groups (p = 0.0227) and in the third CpG site (p = 0.0026). Furthermore, the TD group had lower average methylation levels than HC and NTD groups (p = 0.0115 and 0.0268, respectively). Specifically, TD group showed lower methylation levels in the third CpG site than HC and NTD groups (p = 0.0012 and 0.0072, respectively). Additionally, associations of the methylation levels with clinical features in the TD group were observed using Spearman correlation analysis. CONCLUSION This study provides the first evidence of DNA methylation levels in the promoter of CYP2E1 gene associated with schizophrenia and TD. The abnormal DNA methylation might serve as a potential mechanism for TD.
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Affiliation(s)
- Ping Zhang
- grid.11135.370000 0001 2256 9319Beijing HuiLongGuan Hospital, Peking University HuiLongGuan Clinical Medical School, Beijing, 100096 China
| | - Yanli Li
- grid.11135.370000 0001 2256 9319Beijing HuiLongGuan Hospital, Peking University HuiLongGuan Clinical Medical School, Beijing, 100096 China
| | - Kesheng Wang
- grid.268154.c0000 0001 2156 6140Department of Family and Community Health, Robert C. Byrd Health Sciences Center, School of Nursing, West Virginia University, Morgantown, WV 26506 USA
| | - Junchao Huang
- grid.11135.370000 0001 2256 9319Beijing HuiLongGuan Hospital, Peking University HuiLongGuan Clinical Medical School, Beijing, 100096 China
| | - Brenda Bin Su
- grid.449717.80000 0004 5374 269XDepartment of Health and Biomedical Sciences, College of Health Affairs, University of Texas Rio Grande Valle, Brownsville, TX USA
| | - Chun Xu
- grid.449717.80000 0004 5374 269XDepartment of Health and Biomedical Sciences, College of Health Affairs, University of Texas Rio Grande Valle, Brownsville, TX USA
| | - Zhiren Wang
- grid.11135.370000 0001 2256 9319Beijing HuiLongGuan Hospital, Peking University HuiLongGuan Clinical Medical School, Beijing, 100096 China
| | - Shuping Tan
- grid.11135.370000 0001 2256 9319Beijing HuiLongGuan Hospital, Peking University HuiLongGuan Clinical Medical School, Beijing, 100096 China
| | - Fude Yang
- grid.11135.370000 0001 2256 9319Beijing HuiLongGuan Hospital, Peking University HuiLongGuan Clinical Medical School, Beijing, 100096 China
| | - Yunlong Tan
- grid.11135.370000 0001 2256 9319Beijing HuiLongGuan Hospital, Peking University HuiLongGuan Clinical Medical School, Beijing, 100096 China
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15
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The stress-vulnerability model on the path to schizophrenia: Interaction between BDNF methylation and schizotypy on the resting-state brain network. SCHIZOPHRENIA 2022; 8:49. [PMID: 35853898 PMCID: PMC9261098 DOI: 10.1038/s41537-022-00258-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 04/25/2022] [Indexed: 11/08/2022]
Abstract
The interplay between schizophrenia liability and environmental influences has been considered to be responsible for the development of schizophrenia. Recent neuroimaging studies have linked aberrant functional connectivity (FC) between the default-mode network (DMN) and the frontoparietal network (FPN) in the resting-state to the underlying neural mechanism of schizophrenia. By using schizotypy as the proxy for genetic-based liability to schizophrenia and methylation of brain-derived neurotrophic factor (BDNF) to represent environmental exposure, this study investigated the impact of the interaction between vulnerability and the environment on the neurobiological substrates of schizophrenia. Participants in this study included 101 healthy adults (HC) and 46 individuals with ultra-high risk for psychosis (UHR). All participants were tested at resting-state by functional magnetic resonance imaging, and group-independent component analysis was used to identify the DMN and the FPN. The Perceptual Aberration Scale (PAS) was used to evaluate the schizotypy level. The methylation status of BDNF was measured by pyrosequencing. For moderation analysis, the final sample consisted of 83 HC and 32 UHR individuals. UHR individuals showed reduced DMN-FPN network FC compared to healthy controls. PAS scores significantly moderated the relationship between the percentage of BDNF methylation and DMN-FPN network FC. The strength of the positive relationship between BDNF methylation and the network FC was reduced when the schizotypy level increased. These findings support the moderating role of schizotypy on the neurobiological mechanism of schizophrenia in conjunction with epigenetic changes.
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16
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Huang H, Yang L, Liu Y, Dong GH, Chen L, Li S, Guo Y, Xie B, Chen G. Long-term ambient air pollution exposure and DNA methylation of peripheral brain-derived neurotrophic factor promoter. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 244:114061. [PMID: 36088717 DOI: 10.1016/j.ecoenv.2022.114061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 08/18/2022] [Accepted: 09/04/2022] [Indexed: 06/15/2023]
Abstract
This study aimed to investigate the association between air pollutants and methylation of peripheral brain-derived neurotrophic factor (BDNF) promoters. A total of 101 individuals were recruited in this panel study. BDNF promoter methylation was detected by bisulfite-PCR amplification and pyrosequencing. Participants' exposure to air pollutants was estimated using a satellite-based random forests approach. A generalized estimated equation model with natural cubic splines was employed to examine the associations between air pollutants and BDNF promoter methylation levels. The associations between air pollution and BDNF promoter methylation showed nonlinear curves with threshold effects. The threshold concentration for the association of nitrogen dioxide (NO2) with average methylation level was 59.7 μg/m3, and that for the association of particulate matter ≤ 1 µm in diameter (PM1) with CpG2 methylation level was 70.9 μg/m3. The percent change of average methylation level at the 95th percentile of NO2 against the threshold concentration was 43.25% (95%CI: 13.10%, 73.40%), and that of CpG2 methylation at the 95th percentile of PM1 was 128.29% (95%CI: 43.27%, 213.31%). Overall, long-term exposures of PM1, PM2.5, PM10, and NO2 were associated with significant changes in BDNF promoter methylation levels with threshold effects.
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Affiliation(s)
- Haoyu Huang
- Department of Occupational and Environmental Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Lei Yang
- Department of Epidemiology and Statistics, School of Public Health, Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Shijiazhuang 050017, China
| | - Yuewei Liu
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Guang-Hui Dong
- Department of Occupational and Environmental Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Lijun Chen
- College of Information Engineering, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Shanshan Li
- Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Yuming Guo
- Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Bing Xie
- College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang 050017, China.
| | - Gongbo Chen
- Department of Occupational and Environmental Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
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17
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Govender P, Ghai M, Okpeku M. Sex-specific DNA methylation: impact on human health and development. Mol Genet Genomics 2022; 297:1451-1466. [PMID: 35969270 DOI: 10.1007/s00438-022-01935-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 07/28/2022] [Indexed: 11/26/2022]
Abstract
Human evolution has shaped gender differences between males and females. Over the years, scientific studies have proposed that epigenetic modifications significantly influence sex-specific differences. The evolution of sex chromosomes with epigenetics as the driving force may have led to one sex being more adaptable than the other when exposed to various factors over time. Identifying and understanding sex-specific differences, particularly in DNA methylation, will help determine how each gender responds to factors, such as disease susceptibility, environmental exposure, brain development and neurodegeneration. From a medicine and health standpoint, sex-specific methylation studies have shed light on human disease severity, progression, and response to therapeutic intervention. Interesting findings in gender incongruent individuals highlight the role of genetic makeup in influencing DNA methylation differences. Sex-specific DNA methylation studies will empower the biotechnology and pharmaceutical industry with more knowledge to identify biomarkers, design and develop sex bias drugs leading to better treatment in men and women based on their response to different diseases.
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Affiliation(s)
- Priyanka Govender
- Discipline of Genetics, School of Life Sciences, University of KwaZulu-Natal, Westville, South Africa
| | - Meenu Ghai
- Discipline of Genetics, School of Life Sciences, University of KwaZulu-Natal, Westville, South Africa.
| | - Moses Okpeku
- Discipline of Genetics, School of Life Sciences, University of KwaZulu-Natal, Westville, South Africa
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18
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Rodríguez-Carrillo A, D'Cruz SC, Mustieles V, Suárez B, Smagulova F, David A, Peinado F, Artacho-Cordón F, López LC, Arrebola JP, Olea N, Fernández MF, Freire C. Exposure to non-persistent pesticides, BDNF, and behavioral function in adolescent males: Exploring a novel effect biomarker approach. ENVIRONMENTAL RESEARCH 2022; 211:113115. [PMID: 35292247 DOI: 10.1016/j.envres.2022.113115] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/02/2022] [Accepted: 03/10/2022] [Indexed: 05/22/2023]
Abstract
BACKGROUND Numerous contemporary non-persistent pesticides may elicit neurodevelopmental impairments. Brain-derived neurotrophic factor (BDNF) has been proposed as a novel effect biomarker of neurological function that could help to understand the biological responses of some environmental exposures. OBJECTIVES To investigate the relationship between exposure to various non-persistent pesticides, BDNF, and behavioral functioning among adolescents. METHODS The concentrations of organophosphate (OP) insecticide metabolites 3,5,6-trichloro-2-pyridinol (TCPy), 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPy), malathion diacid (MDA), and diethyl thiophosphate (DETP); metabolites of pyrethroids 3-phenoxybenzoic acid (3-PBA) and dimethylcyclopropane carboxylic acid (DCCA), the metabolite of insecticide carbaryl 1-naphthol (1-N), and the metabolite of ethylene-bis-dithiocarbamate fungicides ethylene thiourea (ETU) were measured in spot urine samples, as well as serum BDNF protein levels and blood DNA methylation of Exon IV of BDNF gene in 15-17-year-old boys from the INMA-Granada cohort in Spain. Adolescents' behavior was reported by parents using the Child Behavior Check List (CBCL/6-18). This study included 140 adolescents of whom 118 had data on BDNF gene DNA methylation. Multivariable linear regression, weighted quantile sum (WQS) for mixture effects, and mediation models were fit. RESULTS IMPy, MDA, DCCA, and ETU were detected in more than 70% of urine samples, DETP in 53%, and TCPy, 3-PBA, and 1-N in less than 50% of samples. Higher levels of IMPy, TCPy, and ETU were significantly associated with more behavioral problems as social, thought problems, and rule-breaking symptoms. IMPy, MDA, DETP, and 1-N were significantly associated with decreased serum BDNF levels, while MDA, 3-PBA, and ETU were associated with higher DNA methylation percentages at several CpGs. WQS models suggest a mixture effect on more behavioral problems and BDNF DNA methylation at several CpGs. A mediated effect of serum BDNF within IMPy-thought and IMPy-rule breaking associations was suggested. CONCLUSION BDNF biomarkers measured at different levels of biological complexity provided novel information regarding the potential disruption of behavioral function due to contemporary pesticides, highlighting exposure to diazinon (IMPy) and the combined effect of IMPy, MDA, DCCA, and ETU. However, further research is warranted.
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Affiliation(s)
- Andrea Rodríguez-Carrillo
- University of Granada, Biomedical Research Center (CIBM), Department of Radiology, 18016, Granada, Spain
| | - Shereen C D'Cruz
- Univ Rennes, EHESP, INSERM, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, F-35000, Rennes, France
| | - Vicente Mustieles
- University of Granada, Biomedical Research Center (CIBM), Department of Radiology, 18016, Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Spain
| | - Beatriz Suárez
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain
| | - Fátima Smagulova
- Univ Rennes, EHESP, INSERM, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, F-35000, Rennes, France
| | - Arthur David
- Univ Rennes, EHESP, INSERM, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, F-35000, Rennes, France
| | - Francisco Peinado
- University of Granada, Biomedical Research Center (CIBM), Department of Radiology, 18016, Granada, Spain
| | - Francisco Artacho-Cordón
- University of Granada, Biomedical Research Center (CIBM), Department of Radiology, 18016, Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Spain
| | - Luis C López
- University of Granada, Department of Physiology, 18016, Granada, Spain
| | - Juan P Arrebola
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Spain; University of Granada, Department of Preventive Medicine and Public Health, 18016, Granada, Spain
| | - Nicolás Olea
- University of Granada, Biomedical Research Center (CIBM), Department of Radiology, 18016, Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Spain
| | - Mariana F Fernández
- University of Granada, Biomedical Research Center (CIBM), Department of Radiology, 18016, Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Spain.
| | - Carmen Freire
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Spain
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19
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Lockwood L, Miller B, Youssef NA. Epigenetics and first-episode psychosis: A systematic review. Psychiatry Res 2022; 307:114325. [PMID: 34896847 DOI: 10.1016/j.psychres.2021.114325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 11/24/2021] [Accepted: 12/03/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND Schizophrenia has a large disease burden globally. Early intervention in psychosis, and therefore a decreased duration of untreated psychosis, has a positive clinical impact. There are several recognized risk factors for psychosis, including trauma history and substance use. This systematic review examined the literature for studies related to epigenetic changes in first-episode psychosis, with the goal of identifying future research directions. METHODS A literature review was conducted from inception to October 3, 2021 using MedLine/PubMed, Web of Science, and PsycInfo searches with the keywords ("first-episode schizophrenia" OR "first-episode psychosis" OR "drug-naive schizophrenia" OR "drug-naive psychosis") AND (epigenetic OR methylation OR hydroxymethylation OR "histone modification" OR "miRNA") as well as a search of the bibliography of the identified papers. RESULTS Seventeen studies that examined various portions of the genome were included in this systematic review. There were two studies that showed hypomethylation at the LINE-1 portion of the genome and two that showed hypermethylation at LINE-1. Additionally, two studies showed hypomethylation specifically at the GRIN2B promoter (part of LINE-1). CONCLUSIONS Although sample sizes were small, these studies provide evidence for epigenetic alterations in early psychosis. Further research in this area is warranted for more definitive epigenetic correlations.
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Affiliation(s)
| | - Brian Miller
- Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta, GA, USA
| | - Nagy A Youssef
- Department of Psychiatry and Health Behavior, Ohio State University, Columbus, OH, USA
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20
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Ropret S, Kouter K, Zupanc T, Videtic Paska A. BDNF methylation and mRNA expression in brain and blood of completed suicides in Slovenia. World J Psychiatry 2021; 11:1301-1313. [PMID: 35070779 PMCID: PMC8717036 DOI: 10.5498/wjp.v11.i12.1301] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/25/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Suicide is a major public health problem. Worldwide, around 800000 people die by suicide every year. Suicide is a multifactorial disorder, with numerous environmental and genetic risk factors involved. Among the candidate genes, changes in the BDNF locus at the gene, epigenetic, mRNA, and protein expression levels have been implicated in psychiatric disorders, including suicidal behavior and completed suicides. AIM To investigate changes in BDNF methylation and expression of four alternative BDNF transcripts for association with completed suicide. METHODS This case-control study included 42 unrelated male Caucasian subjects, where 20 were control subjects who died following acute cardiac arrest, and 22 were suicide victims who died by hanging. DNA and RNA were extracted from brain tissue (Brodmann area 9 and hippocampus) and from blood. DNA methylation and mRNA expression levels were determined by targeted bisulfite next-generation sequencing and reverse-transcription quantitative PCR. Statistical analysis was done by use of two-tailed Student's t tests for two independent samples, and the Benjamini-Hochberg procedure was implemented for correction for multiple comparisons. RESULTS In DNA from brain tissue, there were no significant differences in BDNF methylation between the study groups. However, data showed significantly reduced DNA methylation of the BDNF region upstream of exon I in blood samples of suicide victims compared to the controls (5.67 ± 0.57 vs 6.83 ± 0.64, P corr = 0.01). In Brodmann area 9 of the brain of the suicide victims but not in their hippocampus, there was higher expression of BDNF transcript I-IX (NM_170731.4) compared to the controls (0.077 ± 0.024 vs 0.05 ± 0.013, P = 0.042). In blood, expression analysis for the BDNF transcripts was not feasible due to extensive RNA degradation. CONCLUSION Despite the limitations of the study, the obtained data further support a role for BDNF in suicidality. However, it should be noted that suicidal behavior is a multifactorial disorder with numerous environmental and genetic risk factors involved.
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Affiliation(s)
- Sandra Ropret
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana SI-1000, Slovenia
| | - Katarina Kouter
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana SI-1000, Slovenia
| | - Tomaž Zupanc
- Institute of Forensic Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana SI-1000, Slovenia
| | - Alja Videtic Paska
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana SI-1000, Slovenia
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21
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Bandeira IC, Giombelli L, Werlang IC, Abujamra AL, Secchi TL, Brondani R, Bragatti JA, Bizzi JWJ, Leistner-Segal S, Bianchin MM. Methylation of BDNF and SLC6A4 Gene Promoters in Brazilian Patients With Temporal Lobe Epilepsy Presenting or Not Psychiatric Comorbidities. Front Integr Neurosci 2021; 15:764742. [PMID: 34912196 PMCID: PMC8667271 DOI: 10.3389/fnint.2021.764742] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 10/25/2021] [Indexed: 01/09/2023] Open
Abstract
The relationship between epilepsy and psychiatric comorbidities has been recognized for centuries, but its pathophysiological mechanisms are still misunderstood. It is biologically plausible that genetic or epigenetic variations in genes that codify important neurotransmitters involved in epilepsy as well as in psychiatric disorders may influence the development of the latter in patients with epilepsy. However, this possibility remains poorly investigated. The aim of this study was to evaluate the methylation profile of the BDNF and SLC6A4, two genes importantly involved in neuroplasticity, in patients with temporal lobe epilepsy (TLE) regarding the development or not of psychiatric comorbidities. One hundred and thirty-nine patients with TLE, 90 females and 45 males, were included in the study. The mean age of patients was 44.0 (+12.0) years, and mean duration of epilepsy was 25.7 (+13.3) years. The Structured Clinical Interview for DSM-IV shows that 83 patients (59.7%) had neuropsychiatric disorders and 56 (40.3%) showed no psychiatric comorbidity. Mood disorders were the most common psychiatric disorder observed, being present in 64 (46.0%) of all 139 patients. Thirty-three (23.7%) patients showed anxiety disorders, 10 (7.2%) patients showed history of psychosis and 8 (5.8%) patients showed history of alcohol//drug abuse. Considering all 139 patients, 18 (12.9%) demonstrated methylation of the promoter region of both BDNF and SLC6A4 genes. A significant decreased methylation profile was observed only in TLE patients with mood disorders when compared with TLE patients without a history of mood disorders (O.R. = 3.45; 95% C.I. = 1.08–11.11; p = 0.04). A sub-analysis showed that TLE patients with major depressive disorder mostly account for this result (O.R. = 7.20; 95% C.I. = 1.01–56.16; p = 0.042). A logistic regression analysis showed that the independent factors associated with a history of depression in our TLE patients was female sex (O.R. = 2.30; 95% C.I. = 1.02–5.18; p = 0.044), not controlled seizures (O.R. = 2.51; 95% C.I. = 1.16–5.41; p = 0.019) and decreased methylation in BDNF and SLC6A4 genes (O.R. = 5.32; 95% C.I. = 1.14–25.00; p = 0.033). Our results suggest that BDNF or SLC6A4 genes profile methylation is independently associated with depressive disorders in patients with epilepsy. Further studies are necessary to clarify these matters.
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Affiliation(s)
- Isabel Cristina Bandeira
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Basic Research and Advanced Investigations in Neurosciences, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Lucas Giombelli
- Basic Research and Advanced Investigations in Neurosciences, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Isabel Cristina Werlang
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Basic Research and Advanced Investigations in Neurosciences, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Ana Lucia Abujamra
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Thais Leite Secchi
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Rosane Brondani
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Division of Neurology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | | | | | - Sandra Leistner-Segal
- Basic Research and Advanced Investigations in Neurosciences, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.,Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Marino Muxfeldt Bianchin
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Basic Research and Advanced Investigations in Neurosciences, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.,Division of Neurology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.,Centro de Tratamento de Epilepsia Refratária (CETER), Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
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22
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Li L, Wang T, Chen S, Yue Y, Xu Z, Yuan Y. DNA methylations of brain-derived neurotrophic factor exon VI are associated with major depressive disorder and antidepressant-induced remission in females. J Affect Disord 2021; 295:101-107. [PMID: 34418778 DOI: 10.1016/j.jad.2021.08.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/04/2021] [Accepted: 08/06/2021] [Indexed: 11/17/2022]
Abstract
BACKGROUND Brain-derived neurotrophic factor (BDNF) has been suggested to play important roles in major depressive disorder (MDD) and antidepressant treatment. The main purpose of this study was to evaluate the association of DNA methylation changes in the BDNF gene with MDD and antidepressant treatment. METHODS A total of 291 MDD patients and 100 healthy controls were included and followed up for 6 weeks. The Hamilton Depression Rating Scale-17 (HDRS-17) was used to measure treatment improvement. The life events scales (LES) and childhood trauma questionnaire (CTQ) were used to rate recent and early life stress. DNA methylation levels of CpG sites in the BDNF gene were measured. RESULTS Two CpG sites in BDNF exon VI (BDNF133 and BDNF134) were demonstrated to have significantly higher methylation in MDD patients than in controls (both FDR-adjusted P = 0.001). A logistics regression model indicated that the interaction between the hypermethylation of BDNF133 and negative subscore of LES was associated to MDD (OR=0.0075, P<0.001). Methylation of BDNF140 at baseline was significantly elevated in remitters (FDR-adjusted P = 0.046) at week 6. In subgroup analyses, these findings could be replicated in females, but not in males. LIMITATIONS The methylation status of BDNF after 6 weeks of antidepressant treatment was not measured and the DNA methylation were detected in peripheral blood cells. CONCLUSIONS These findings highlight gender-specific alteration of methylation at several CpG sites in BDNF exon VI as a promising candidate indicator of MDD and antidepressant-induced remission.
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Affiliation(s)
- Lei Li
- Institute of Psychosomatics, School of Medicine, Southeast University, Nanjing, 210023, China; Department of Psychosomatics and Psychiatry, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, China; Department of Sleep Medicine, The Fourth People's Hospital of Lianyungang, Lianyungang, 222000, China
| | - Tianyu Wang
- Institute of Psychosomatics, School of Medicine, Southeast University, Nanjing, 210023, China; Department of Psychosomatics and Psychiatry, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, China
| | - Suzhen Chen
- Institute of Psychosomatics, School of Medicine, Southeast University, Nanjing, 210023, China; Department of Psychosomatics and Psychiatry, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, China
| | - Yingying Yue
- Institute of Psychosomatics, School of Medicine, Southeast University, Nanjing, 210023, China; Department of Psychosomatics and Psychiatry, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, China
| | - Zhi Xu
- Institute of Psychosomatics, School of Medicine, Southeast University, Nanjing, 210023, China; Department of Psychosomatics and Psychiatry, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, China.
| | - Yonggui Yuan
- Institute of Psychosomatics, School of Medicine, Southeast University, Nanjing, 210023, China; Department of Psychosomatics and Psychiatry, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, China; Jiangsu Provincial Key Laboratory of Critical Care Medicine, Southeast university, Nanjing, 210009, China.
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23
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Wagh VV, Vyas P, Agrawal S, Pachpor TA, Paralikar V, Khare SP. Peripheral Blood-Based Gene Expression Studies in Schizophrenia: A Systematic Review. Front Genet 2021; 12:736483. [PMID: 34721526 PMCID: PMC8548640 DOI: 10.3389/fgene.2021.736483] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/31/2021] [Indexed: 12/19/2022] Open
Abstract
Schizophrenia is a disorder that is characterized by delusions, hallucinations, disorganized speech or behavior, and socio-occupational impairment. The duration of observation and variability in symptoms can make the accurate diagnosis difficult. Identification of biomarkers for schizophrenia (SCZ) can help in early diagnosis, ascertaining the diagnosis, and development of effective treatment strategies. Here we review peripheral blood-based gene expression studies for identification of gene expression biomarkers for SCZ. A literature search was carried out in PubMed and Web of Science databases for blood-based gene expression studies in SCZ. A list of differentially expressed genes (DEGs) was compiled and analyzed for overlap with genetic markers, differences based on drug status of the participants, functional enrichment, and for effect of antipsychotics. This literature survey identified 61 gene expression studies. Seventeen out of these studies were based on expression microarrays. A comparative analysis of the DEGs (n = 227) from microarray studies revealed differences between drug-naive and drug-treated SCZ participants. We found that of the 227 DEGs, 11 genes (ACOT7, AGO2, DISC1, LDB1, RUNX3, SIGIRR, SLC18A1, NRG1, CHRNB2, PRKAB2, and ZNF74) also showed genetic and epigenetic changes associated with SCZ. Functional enrichment analysis of the DEGs revealed dysregulation of proline and 4-hydroxyproline metabolism. Also, arginine and proline metabolism was the most functionally enriched pathway for SCZ in our analysis. Follow-up studies identified effect of antipsychotic treatment on peripheral blood gene expression. Of the 27 genes compiled from the follow-up studies AKT1, DISC1, HP, and EIF2D had no effect on their expression status as a result of antipsychotic treatment. Despite the differences in the nature of the study, ethnicity of the population, and the gene expression analysis method used, we identified several coherent observations. An overlap, though limited, of genetic, epigenetic and gene expression changes supports interplay of genetic and environmental factors in SCZ. The studies validate the use of blood as a surrogate tissue for biomarker analysis. We conclude that well-designed cohort studies across diverse populations, use of high-throughput sequencing technology, and use of artificial intelligence (AI) based computational analysis will significantly improve our understanding and diagnostic capabilities for this complex disorder.
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Affiliation(s)
- Vipul Vilas Wagh
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Parin Vyas
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Suchita Agrawal
- The Psychiatry Unit, KEM Hospital and KEM Hospital Research Centre, Pune, India
| | | | - Vasudeo Paralikar
- The Psychiatry Unit, KEM Hospital and KEM Hospital Research Centre, Pune, India
| | - Satyajeet P Khare
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
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24
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Magwai T, Shangase KB, Oginga FO, Chiliza B, Mpofana T, Xulu KR. DNA Methylation and Schizophrenia: Current Literature and Future Perspective. Cells 2021; 10:2890. [PMID: 34831111 PMCID: PMC8616184 DOI: 10.3390/cells10112890] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/09/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022] Open
Abstract
Schizophrenia is a neuropsychiatric disorder characterized by dissociation of thoughts, idea, identity, and emotions. It has no central pathophysiological mechanism and precise diagnostic markers. Despite its high heritability, there are also environmental factors implicated in the development of schizophrenia. Epigenetic factors are thought to mediate the effects of environmental factors in the development of the disorder. Epigenetic modifications like DNA methylation are a risk factor for schizophrenia. Targeted gene approach studies attempted to find candidate gene methylation, but the results are contradictory. Genome-wide methylation studies are insufficient in literature and the available data do not cover different populations like the African populations. The current genome-wide studies have limitations related to the sample and methods used. Studies are required to control for these limitations. Integration of DNA methylation, gene expression, and their effects are important in the understanding of the development of schizophrenia and search for biomarkers. There are currently no precise and functional biomarkers for the disorder. Several epigenetic markers have been reported to be common in functional and peripheral tissue. This makes the peripheral tissue epigenetic changes a surrogate of functional tissue, suggesting common epigenetic alteration can be used as biomarkers of schizophrenia in peripheral tissue.
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Affiliation(s)
- Thabo Magwai
- Department of Physiology, School of Laboratory Medicine and Medical Sciences, University of Kwa-Zulu Natal, Durban 4001, South Africa; (K.B.S.); (F.O.O.); (T.M.)
- National Health Laboratory Service, Department of Chemical Pathology, University of Kwa-Zulu Natal, Durban 4085, South Africa
| | - Khanyiso Bright Shangase
- Department of Physiology, School of Laboratory Medicine and Medical Sciences, University of Kwa-Zulu Natal, Durban 4001, South Africa; (K.B.S.); (F.O.O.); (T.M.)
| | - Fredrick Otieno Oginga
- Department of Physiology, School of Laboratory Medicine and Medical Sciences, University of Kwa-Zulu Natal, Durban 4001, South Africa; (K.B.S.); (F.O.O.); (T.M.)
| | - Bonginkosi Chiliza
- Department of Psychiatry, Nelson R Mandela School of Medicine, University of Kwa-Zulu Natal, Durban 4001, South Africa;
| | - Thabisile Mpofana
- Department of Physiology, School of Laboratory Medicine and Medical Sciences, University of Kwa-Zulu Natal, Durban 4001, South Africa; (K.B.S.); (F.O.O.); (T.M.)
| | - Khethelo Richman Xulu
- Department of Physiology, School of Laboratory Medicine and Medical Sciences, University of Kwa-Zulu Natal, Durban 4001, South Africa; (K.B.S.); (F.O.O.); (T.M.)
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25
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Buck JM, Yu L, Knopik VS, Stitzel JA. DNA methylome perturbations: an epigenetic basis for the emergingly heritable neurodevelopmental abnormalities associated with maternal smoking and maternal nicotine exposure†. Biol Reprod 2021; 105:644-666. [PMID: 34270696 PMCID: PMC8444709 DOI: 10.1093/biolre/ioab138] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 06/29/2021] [Accepted: 07/14/2021] [Indexed: 11/13/2022] Open
Abstract
Maternal smoking during pregnancy is associated with an ensemble of neurodevelopmental consequences in children and therefore constitutes a pressing public health concern. Adding to this burden, contemporary epidemiological and especially animal model research suggests that grandmaternal smoking is similarly associated with neurodevelopmental abnormalities in grandchildren, indicative of intergenerational transmission of the neurodevelopmental impacts of maternal smoking. Probing the mechanistic bases of neurodevelopmental anomalies in the children of maternal smokers and the intergenerational transmission thereof, emerging research intimates that epigenetic changes, namely DNA methylome perturbations, are key factors. Altogether, these findings warrant future research to fully elucidate the etiology of neurodevelopmental impairments in the children and grandchildren of maternal smokers and underscore the clear potential thereof to benefit public health by informing the development and implementation of preventative measures, prophylactics, and treatments. To this end, the present review aims to encapsulate the burgeoning evidence linking maternal smoking to intergenerational epigenetic inheritance of neurodevelopmental abnormalities, to identify the strengths and weaknesses thereof, and to highlight areas of emphasis for future human and animal model research therein.
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Affiliation(s)
- Jordan M Buck
- Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA
- Department of Integrative Physiology, University of Colorado, Boulder, Boulder, CO, USA
| | - Li Yu
- Department of Human Development and Family Studies, Purdue University, West Lafayette, IN, USA
| | - Valerie S Knopik
- Department of Human Development and Family Studies, Purdue University, West Lafayette, IN, USA
| | - Jerry A Stitzel
- Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA
- Department of Integrative Physiology, University of Colorado, Boulder, Boulder, CO, USA
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26
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Hidden Role of Gut Microbiome Dysbiosis in Schizophrenia: Antipsychotics or Psychobiotics as Therapeutics? Int J Mol Sci 2021; 22:ijms22147671. [PMID: 34299291 PMCID: PMC8307070 DOI: 10.3390/ijms22147671] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/14/2021] [Accepted: 07/15/2021] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia is a chronic, heterogeneous neurodevelopmental disorder that has complex symptoms and uncertain etiology. Mounting evidence indicates the involvement of genetics and epigenetic disturbances, alteration in gut microbiome, immune system abnormalities, and environmental influence in the disease, but a single root cause and mechanism involved has yet to be conclusively determined. Consequently, the identification of diagnostic markers and the development of psychotic drugs for the treatment of schizophrenia faces a high failure rate. This article surveys the etiology of schizophrenia with a particular focus on gut microbiota regulation and the microbial signaling system that correlates with the brain through the vagus nerve, enteric nervous system, immune system, and production of postbiotics. Gut microbially produced molecules may lay the groundwork for further investigations into the role of gut microbiota dysbiosis and the pathophysiology of schizophrenia. Current treatment of schizophrenia is limited to psychotherapy and antipsychotic drugs that have significant side effects. Therefore, alternative therapeutic options merit exploration. The use of psychobiotics alone or in combination with antipsychotics may promote the development of novel therapeutic strategies. In view of the individual gut microbiome structure and personalized response to antipsychotic drugs, a tailored and targeted manipulation of gut microbial diversity naturally by novel prebiotics (non-digestible fiber) may be a successful alternative therapeutic for the treatment of schizophrenia patients.
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27
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Munawar N, Ahsan K, Muhammad K, Ahmad A, Anwar MA, Shah I, Al Ameri AK, Al Mughairbi F. Hidden Role of Gut Microbiome Dysbiosis in Schizophrenia: Antipsychotics or Psychobiotics as Therapeutics? Int J Mol Sci 2021. [DOI: https://doi.org/10.3390/ijms22147671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Schizophrenia is a chronic, heterogeneous neurodevelopmental disorder that has complex symptoms and uncertain etiology. Mounting evidence indicates the involvement of genetics and epigenetic disturbances, alteration in gut microbiome, immune system abnormalities, and environmental influence in the disease, but a single root cause and mechanism involved has yet to be conclusively determined. Consequently, the identification of diagnostic markers and the development of psychotic drugs for the treatment of schizophrenia faces a high failure rate. This article surveys the etiology of schizophrenia with a particular focus on gut microbiota regulation and the microbial signaling system that correlates with the brain through the vagus nerve, enteric nervous system, immune system, and production of postbiotics. Gut microbially produced molecules may lay the groundwork for further investigations into the role of gut microbiota dysbiosis and the pathophysiology of schizophrenia. Current treatment of schizophrenia is limited to psychotherapy and antipsychotic drugs that have significant side effects. Therefore, alternative therapeutic options merit exploration. The use of psychobiotics alone or in combination with antipsychotics may promote the development of novel therapeutic strategies. In view of the individual gut microbiome structure and personalized response to antipsychotic drugs, a tailored and targeted manipulation of gut microbial diversity naturally by novel prebiotics (non-digestible fiber) may be a successful alternative therapeutic for the treatment of schizophrenia patients.
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28
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Rygiel CA, Dolinoy DC, Bakulski KM, Aung MT, Perng W, Jones TR, Solano-González M, Hu H, Tellez-Rojo MM, Schnaas L, Marcela E, Peterson KE, Goodrich JM. DNA methylation at birth potentially mediates the association between prenatal lead (Pb) exposure and infant neurodevelopmental outcomes. ENVIRONMENTAL EPIGENETICS 2021; 7:dvab005. [PMID: 34141453 PMCID: PMC8206046 DOI: 10.1093/eep/dvab005] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/30/2021] [Accepted: 04/16/2021] [Indexed: 05/08/2023]
Abstract
Early-life lead (Pb) exposure has been linked to adverse neurodevelopmental outcomes. Recent evidence has indicated a critical role of DNA methylation (DNAm) in cognition, and Pb exposure has also been shown to alter DNAm. However, it is unknown whether DNAm is part of the mechanism of Pb neurotoxicity. This longitudinal study investigated the associations between trimester-specific (T1, T2, and T3) maternal blood Pb concentrations, gene-specific DNAm in umbilical cord blood, and infant neurodevelopmental outcomes at 12 and 24 months of age (mental development index, psychomotor development index, and behavioral rating scale of orientation/engagement and emotional regulation) among 85 mother-infant pairs from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) study. In the mediation analysis for this pilot study, P < 0.1 was considered significant. DNAm at a locus in CCSER1 (probe ID cg02901723) mediated the association between T2 Pb on 24-month orientation/engagement [indirect effect estimate 4.44, 95% confidence interval (-0.09, 10.68), P = 0.06] and emotional regulation [3.62 (-0.05, 8.69), P = 0.05]. Cg18515027 (GCNT1) DNAm mediated the association of T1 Pb [-4.94 (-10.6, -0.77), P = 0.01] and T2 Pb [-3.52 (-8.09, -0.36), P = 0.02] with 24-month EMOCI, but there was a positive indirect effect estimate between T2 Pb and 24-month psychomotor development index [1.25 (-0.11, 3.32), P = 0.09]. The indirect effect was significant for cg19703494 (TRAPPC6A) DNAm in the association between T2 Pb and 24-month mental development index [1.54 (0, 3.87), P = 0.05]. There was also an indirect effect of cg23280166 (VPS11) DNAm on T3 Pb and 24-month EMOCI [2.43 (-0.16, 6.38), P = 0.08]. These associations provide preliminary evidence for gene-specific DNAm as mediators between prenatal Pb and adverse cognitive outcomes in offspring.
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Affiliation(s)
- Christine A Rygiel
- Department of Environmental Health Sciences, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA
| | - Dana C Dolinoy
- Department of Environmental Health Sciences, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA
- Department of Nutritional Sciences, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA
| | - Kelly M Bakulski
- Department of Epidemiology, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA
| | - Max T Aung
- Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, 490 Illinois Street, San Francisco, CA 94143, USA
| | - Wei Perng
- Department of Nutritional Sciences, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA
- Department of Epidemiology and the Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center Colorado School of Public Health, University of Colorado Denver Anschutz Medical Center, 12474 East 19th Avenue, Aurora, CO 80045, USA
| | - Tamara R Jones
- Department of Environmental Health Sciences, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA
| | - Maritsa Solano-González
- Center for Nutrition and Health Research, National Institute of Public Health, Universidad No. 655 Colonia Santa María Ahuacatitlán, Cerrada Los Pinos y Caminera C.P. 62100, Cuernavaca, Morelos, México
| | - Howard Hu
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2001 N. Soto St., Los Angeles, CA 90033, USA
| | - Martha M Tellez-Rojo
- Center for Nutrition and Health Research, National Institute of Public Health, Universidad No. 655 Colonia Santa María Ahuacatitlán, Cerrada Los Pinos y Caminera C.P. 62100, Cuernavaca, Morelos, México
| | - Lourdes Schnaas
- National Institute of Perinatology, Mexico City, Calle Montes Urales 800, Lomas - Virreyes, Lomas de Chapultepec IV Secc, Miguel Hidalgo, 11000 Ciudad de México, CDMX, Mexico
| | - Erika Marcela
- National Institute of Perinatology, Mexico City, Calle Montes Urales 800, Lomas - Virreyes, Lomas de Chapultepec IV Secc, Miguel Hidalgo, 11000 Ciudad de México, CDMX, Mexico
| | - Karen E Peterson
- Department of Environmental Health Sciences, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA
- Department of Nutritional Sciences, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA
| | - Jaclyn M Goodrich
- Department of Environmental Health Sciences, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA
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Early-life stress effects on BDNF DNA methylation in first-episode psychosis and in rats reared in isolation. Prog Neuropsychopharmacol Biol Psychiatry 2021; 108:110188. [PMID: 33259836 DOI: 10.1016/j.pnpbp.2020.110188] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/26/2020] [Accepted: 11/23/2020] [Indexed: 12/11/2022]
Abstract
Stressful events during early-life are risk factors for psychiatric disorders. Brain-derived neurotrophic factor (BDNF) is implicated in psychosis pathophysiology and deficits in BDNF mRNA in animal models of psychiatric disease are reported. DNA methylation can control gene expression and may be influenced by environmental factors such as early-life stress. We investigated BDNF methylation in first-episode psychosis (FEP) patients (n = 58), their unaffected siblings (n = 29) and community-based controls (n = 59), each of whom completed the Childhood Trauma Questionnaire (CTQ); BDNF methylation was also tested in male Wistar rats housed isolated or grouped from weaning. DNA was extracted from human blood and rat brain (prefrontal cortex and hippocampus), bisulphite-converted and the methylation of equivalent sequences within BDNF exon IV determined by pyrosequencing. BDNF methylation did not differ significantly between diagnostic groups; however, individuals who had experienced trauma presented higher levels of methylation. We found association between the mean BDNF methylation and total CTQ score in FEP, as well as between individual CpG sites and subtypes of trauma. No significant correlations were found for controls or siblings with child trauma. These results were independent of age, gender, body mass index, BDNF genotype or LINE-1, a measure of global methylation, which showed no significant association with trauma. Isolation rearing resulted in increased BDNF methylation in both brain regions compared to group-housed animals, a correlate of previously reported changes in gene expression. Our results suggest that childhood maltreatment may result in increased BDNF methylation, providing a mechanism underlying the association between early-life stress and psychosis.
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Lisoway AJ, Chen CC, Zai CC, Tiwari AK, Kennedy JL. Toward personalized medicine in schizophrenia: Genetics and epigenetics of antipsychotic treatment. Schizophr Res 2021; 232:112-124. [PMID: 34049235 DOI: 10.1016/j.schres.2021.05.010] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 04/30/2021] [Accepted: 05/02/2021] [Indexed: 12/21/2022]
Abstract
Schizophrenia is a complex psychiatric disorder where genetic, epigenetic, and environmental factors play a role in disease onset, course of illness, and treatment outcome. Pharmaco(epi)genetic research presents an important opportunity to improve patient care through prediction of medication side effects and response. In this narrative review, we discuss the current state of research and important progress of both genetic and epigenetic factors involved in antipsychotic response, over the past five years. The review is largely focused on the following frequently prescribed antipsychotics: olanzapine, risperidone, aripiprazole, and clozapine. Several consistent pharmacogenetic findings have emerged, in particular pharmacokinetic genes (primarily cytochrome P450 enzymes) and pharmacodynamic genes involving dopamine, serotonin, and glutamate neurotransmission. In addition to studies analysing DNA sequence variants, there are also several pharmacoepigenetic studies of antipsychotic response that have focused on the measurement of DNA methylation. Although pharmacoepigenetics is still in its infancy, consideration of both genetic and epigenetic factors contributing to antipsychotic response and side effects no doubt will be increasingly important in personalized medicine. We provide recommendations for next steps in research and clinical evaluation.
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Affiliation(s)
- Amanda J Lisoway
- Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Canada
| | - Cheng C Chen
- Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Canada
| | - Clement C Zai
- Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada; Department of Psychiatry, University of Toronto, Canada
| | - Arun K Tiwari
- Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Canada
| | - James L Kennedy
- Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Canada; Department of Psychiatry, University of Toronto, Canada.
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31
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Iamjan SA, Thanoi S, Watiktinkorn P, Fachim H, Dalton CF, Nudmamud-Thanoi S, Reynolds GP. Changes of BDNF exon IV DNA methylation are associated with methamphetamine dependence. Epigenomics 2021; 13:953-965. [PMID: 34008409 DOI: 10.2217/epi-2020-0463] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Aim: We investigated DNA methylation of BDNF in methamphetamine (METH) dependence in humans and an animal model. Materials & methods: BDNF methylation at exon IV was determined by pyrosequencing of blood DNA from METH-dependent and control subjects, and from rat brain following an escalating dose of METH or vehicle. Bdnf expression was determined in rat brain. Results: BDNF methylation was increased in human METH dependence, greatest in subjects with psychosis and in prefrontal cortex of METH-administered rats; rat hippocampus showed reduced Bdnf methylation and increased gene expression. Conclusion: BDNF methylation is abnormal in human METH dependence, especially METH-dependent psychosis, and in METH-administered rats. This may influence BDNF expression and contribute to the neurotoxic effects of METH exposure.
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Affiliation(s)
- Sri-Arun Iamjan
- Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand.,Centre of Excellence in Medical Biotechnology, Naresuan University, Phitsanulok 65000, Thailand.,Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, Chonburi 20131, Thailand
| | - Samur Thanoi
- Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand.,Centre of Excellence in Medical Biotechnology, Naresuan University, Phitsanulok 65000, Thailand
| | | | - Helene Fachim
- Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield S1 1WB, UK.,Department of Endocrinology and Metabolism, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK
| | - Caroline F Dalton
- Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield S1 1WB, UK
| | - Sutisa Nudmamud-Thanoi
- Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand.,Centre of Excellence in Medical Biotechnology, Naresuan University, Phitsanulok 65000, Thailand
| | - Gavin P Reynolds
- Centre of Excellence in Medical Biotechnology, Naresuan University, Phitsanulok 65000, Thailand.,Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield S1 1WB, UK
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Cholewinski T, Pereira D, Moerland M, Jacobs GE. MTORC1 signaling as a biomarker in major depressive disorder and its pharmacological modulation by novel rapid-acting antidepressants. Ther Adv Psychopharmacol 2021; 11:20451253211036814. [PMID: 34733478 PMCID: PMC8558816 DOI: 10.1177/20451253211036814] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 07/16/2021] [Indexed: 12/15/2022] Open
Abstract
Major depressive disorder (MDD) is a multifactorial psychiatric disorder with obscure pathophysiology. A biomarker-based approach in combination with standardized interview-based instruments is needed to identify MDD subtypes and novel therapeutic targets. Recent findings support the impairment of the mammalian target of rapamycin complex 1 (mTORC1) in MDD. No well-established biomarkers of mTORC1 disease- and treatment-modulated activity are currently available for use in early phase antidepressant drug (AD) development. This review aims to summarize biomarkers of mTORC1 activity in MDD and to suggest how these could be implemented in future early clinical trials on mTORC1 modulating ADs. Therefore, a PubMed-based narrative literature review of the mTORC1 involvement in MDD was performed. We have summarized recent pre-clinical and clinical findings linking the MDD to the impaired activity of several key biomarkers related to mTORC1. Also, cases of restoration of these impairments by classical ADs and novel fast-acting investigational ADs are summarized. The presented biomarkers may be used to monitor pharmacological effects by novel rapid-acting mTORC1-targeting ADs. Based on findings in the peripheral blood mononuclear cells, we argue that those may serve as an ex vivo model for evaluation of mTORC1 activity and propose the use of the summarized biomarkers for this purpose. This could both facilitate the selection of a pharmacodynamically active dose and guide future early clinical efficacy studies in MDD. In conclusion, this review provides a blueprint for the rational development of rapid-acting mTORC1-targeting ADs.
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Affiliation(s)
| | - Diana Pereira
- Centre for Human Drug Research, Leiden, The Netherlands
| | | | - Gabriel E Jacobs
- Centre for Human Drug Research, Zernikedreef 8, 2333 CL Leiden, The Netherlands
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Fu X, Wang J, Du J, Sun J, Baranova A, Zhang F. BDNF Gene's Role in Schizophrenia: From Risk Allele to Methylation Implications. Front Psychiatry 2020; 11:564277. [PMID: 33384622 PMCID: PMC7769935 DOI: 10.3389/fpsyt.2020.564277] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 11/25/2020] [Indexed: 11/24/2022] Open
Abstract
Background: Schizophrenia (SZ) is a severe chronic mental disorder with complex genetic mechanisms. Brain-derived neurotrophic factor (BDNF) is one of promising candidate genes for SZ, and rs6265 is a non-synonymous single nucleotide polymorphism (SNP) in BDNF. Methods: In this study, we performed a case-control association study of rs6265 in a cohort of Han Chinese population from eastern China, including 1,407 SZ patients and 1,136 healthy controls; and carried out a cis-mQTL (Methylation Quantitative Trait Loci) analysis for BDNF rs6265. Results: We found a positive association of rs6265 with SZ (P = 0.037), with the minor allele (A) of rs6265 conferring a protecting effect for SZ (OR = 0.89). Furthermore, cis-mQTL analysis indicates that rs6265 is associated with several methylation loci surrounding BDNF. Conclusions: Together, our findings provide further evidence to support the involvement of BDNF gene in the genesis of SZ.
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Affiliation(s)
- Xiaoqian Fu
- Department of Clinical Psychology, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, China
| | - Jun Wang
- Department of Psychiatry, Wuxi Mental Health Center of Nanjing Medical University, Wuxi, China
| | - Jianbin Du
- Department of Psychiatry, Wuxi Mental Health Center of Nanjing Medical University, Wuxi, China
| | - Jing Sun
- Department of Psychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
| | - Ancha Baranova
- School of Systems Biology, George Mason University, Fairfax, VA, United States
- Research Centre for Medical Genetics, Moscow, Russia
| | - Fuquan Zhang
- Department of Psychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
- Institute of Neuropsychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
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Bakusic J, Ghosh M, Polli A, Bekaert B, Schaufeli W, Claes S, Godderis L. Epigenetic perspective on the role of brain-derived neurotrophic factor in burnout. Transl Psychiatry 2020; 10:354. [PMID: 33077716 PMCID: PMC7573604 DOI: 10.1038/s41398-020-01037-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 09/11/2020] [Accepted: 10/01/2020] [Indexed: 11/09/2022] Open
Abstract
Brain-derived neurotrophic factor (BDNF) plays a potential role in the neurobiology of burnout, but there are no studies investigating the underlying genetic and epigenetic mechanisms. Our aim is to further explore the role of BDNF in burnout, by focusing on the Val66Met polymorphism and methylation patterns of the BDNF gene and serum BDNF (sBDNF) protein expression. We conducted a cross-sectional study by recruiting 129 individuals (59 with burnout and 70 healthy controls). Participants underwent a clinical interview, psychological assessment and blood sample collection. Polymorphism and DNA methylation were measured on DNA from whole blood, using pyrosequencing and sBDNF levels were measured using ELISA. We found significantly increased methylation of promoter I and IV in the burnout group, which also correlated with burnout symptoms. In addition, DNA methylation of promoter I had a significant negative effect on sBDNF. For DNA methylation of exon IX, we did not find a significant difference between the groups, nor associations with sBDNF. The Val66Met polymorphism neither differed between groups, nor was it associated with sBDNF levels. Finally, we did not observe differences in sBDNF level between the groups. Interestingly, we observed a significant negative association between depressive symptoms and sBDNF levels. The current study is the first to show that BDNF DNA methylation changes might play an important role in downregulation of the BDNF protein levels in burnout. The presence of depressive symptoms might have an additional impact on these changes.
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Affiliation(s)
- Jelena Bakusic
- Centre for Environment and Health, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium.
| | - Manosij Ghosh
- grid.5596.f0000 0001 0668 7884Centre for Environment and Health, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium
| | - Andrea Polli
- grid.5596.f0000 0001 0668 7884Centre for Environment and Health, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium ,grid.8767.e0000 0001 2290 8069Pain in Motion research group (PAIN), Department of Physiotherapy, Human Physiology and Anatomy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Bram Bekaert
- grid.5596.f0000 0001 0668 7884Department of Forensic Medicine, Laboratory of Forensic Genetics and Molecular Archaeology; KU Leuven, Leuven, Belgium
| | - Wilmar Schaufeli
- grid.5596.f0000 0001 0668 7884Work, Organisational and Personnel Psychology, KU Leuven, Leuven, Belgium
| | - Stephan Claes
- grid.5596.f0000 0001 0668 7884Psychiatry Research Group, Department of Neuroscience, KU Leuven, Leuven, Belgium
| | - Lode Godderis
- grid.5596.f0000 0001 0668 7884Centre for Environment and Health, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium ,IDEWE, External Service for Prevention and Protection at Work, Heverlee, Belgium
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Polli A, Ghosh M, Bakusic J, Ickmans K, Monteyne D, Velkeniers B, Bekaert B, Godderis L, Nijs J. DNA Methylation and Brain-Derived Neurotrophic Factor Expression Account for Symptoms and Widespread Hyperalgesia in Patients With Chronic Fatigue Syndrome and Comorbid Fibromyalgia. Arthritis Rheumatol 2020; 72:1936-1944. [PMID: 32562379 DOI: 10.1002/art.41405] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 06/07/2020] [Indexed: 12/16/2022]
Abstract
OBJECTIVE The epigenetics of neurotrophic factors holds the potential to unravel the mechanisms underlying the pathophysiology of complex conditions such as chronic fatigue syndrome (CFS). This study was undertaken to explore the role of brain-derived neurotrophic factor (BDNF) genetics, epigenetics, and protein expression in patients with both CFS and comorbid fibromyalgia (CFS/FM). METHODS A repeated-measures study was conducted in 54 participants (28 patients with CFS/FM and 26 matched healthy controls). Participants underwent a comprehensive assessment, including questionnaires, sensory testing, and blood withdrawal. Serum BDNF (sBDNF) protein levels were measured using enzyme-linked immunosorbent assay, while polymorphism and DNA methylation were measured in blood using pyrosequencing technology. To assess the temporal stability of the measures, participants underwent the same assessment twice within 4 days. RESULTS Repeated-measures mixed linear models were used for between-group analysis, with mean differences and 95% confidence intervals (95% CIs) shown. Compared to controls, serum BNDF was higher in patients with CFS/FM (F = 15.703; mean difference 3.31 ng/ml [95% CI 1.65, 4.96]; P = 0.001), whereas BDNF DNA methylation in exon 9 was lower (F = 7.543; mean difference -2.16% [95% CI -3.93, -0.83]; P = 0.007). BDNF DNA methylation was mediated by the Val66Met (rs6265) polymorphism. Lower methylation in the same region predicted higher sBDNF levels (F = 7.137, β = -0.408 [95% CI -0.711, -0.105]; P = 0.009), which in turn predicted participants' symptoms (F = 14.410, β = 3.747 [95% CI 1.79, 5.71]; P = 0.001) and widespread hyperalgesia (F = 4.147, β = 0.04 [95% CI 0.01, 0.08]; P = 0.044). CONCLUSION Our findings indicate that sBDNF levels are elevated in patients with CFS/FM and that BDNF methylation in exon 9 accounts for the regulation of protein expression. Altered BDNF levels might represent a key mechanism explaining CFS/FM pathophysiology.
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Affiliation(s)
- Andrea Polli
- Vrije Universiteit Brussel, Brussels, Belgium, Katholieke Universiteit Leuven, Leuven, Belgium, and Scientific Research Foundation, Flanders, Belgium
| | - Manosij Ghosh
- Katholieke Universiteit Leuven, Leuven, Belgium, and Scientific Research Foundation, Flanders, Belgium
| | | | - Kelly Ickmans
- Vrije Universiteit Brussel and University Hospital Brussels, Brussels, Belgium, and Scientific Research Foundation, Flanders, Belgium
| | | | | | - Bram Bekaert
- University Hospitals Leuven, and Katholieke Universiteit Leuven, Leuven, Belgium
| | - Lode Godderis
- Katholieke Universiteit Leuven, Leuven, Belgium, and External Service for Prevention and Protection at Work, IDEWE, Heverlee, Belgium
| | - Jo Nijs
- Vrije Universiteit Brussel, Brussels, Belgium, and University Hospital Brussels, Brussels, Belgium
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Baghel MS, Singh B, Patro N, Khanna VK, Patro IK, Thakur MK. Poly (I:C) Exposure in Early Life Alters Methylation of DNA and Acetylation of Histone at Synaptic Plasticity Gene Promoter in Developing Rat Brain Leading to Memory Impairment. Ann Neurosci 2020; 26:35-41. [PMID: 32843831 PMCID: PMC7418573 DOI: 10.1177/0972753120919704] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background: Exposure to adverse environmental conditions such as toxic chemicals, viral infections, and even stress during pregnancy or early life may disrupt the development of normal brain and its functioning leading to incidence of neurodevelopmental disorders at later stages of life. Recently, we reported that poly (I:C) exposure altered synaptic plasticity protein level and impaired memory through activation of microglia cells. Purpose: As epigenetic modifications are involved in memory formation, we have studied methylation of DNA and acetylation of histone at promoters of synaptic plasticity genes in the brain of rats exposed to poly (I:C) during early life. Methods: One dose of poly (I:C) (5 mg/kg bw) was intraperitoneally injected to rat pups on postnatal seventh day. A set of pups exposed to vehicle was included as control. In order to assess methylation of DNA and acetylation of histone at synaptic plasticity gene promoter, we performed qPCR after methylated DNA immunoprecipitation and chromatin immunoprecipitation. Results: Poly (I:C) exposure reduced the level of 5-methylcytosine (5mC) at synaptic plasticity gene (bdnf, arc, and egr1) promoters in the frontal cortex (FC) and hippocampus of 3-week rats, although increased it later in both regions of 12-week rats as compared to respective controls. On contrary, poly (I:C) exposure enhanced acetylation of histone H3K9 (H3K9Ac) at promoters of these genes in both regions of 3-week rats but decreased in 12-week rats. Conclusion: Poly (I:C) exposure altered 5mC and H3K9Ac at synaptic plasticity gene promoters resulting in memory impairment of rats at later life.
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Affiliation(s)
| | - Brijendra Singh
- School of Studies in Neuroscience, Jiwaji University, Gwalior, India
| | - Nisha Patro
- School of Studies in Neuroscience, Jiwaji University, Gwalior, India
| | | | - Ishan Kumar Patro
- School of Studies in Neuroscience, Jiwaji University, Gwalior, India
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Epigenomic Dysregulation in Schizophrenia: In Search of Disease Etiology and Biomarkers. Cells 2020; 9:cells9081837. [PMID: 32764320 PMCID: PMC7463953 DOI: 10.3390/cells9081837] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 07/27/2020] [Accepted: 07/31/2020] [Indexed: 12/13/2022] Open
Abstract
Schizophrenia is a severe psychiatric disorder with a complex array of signs and symptoms that causes very significant disability in young people. While schizophrenia has a strong genetic component, with heritability around 80%, there is also a very significant range of environmental exposures and stressors that have been implicated in disease development and neuropathology, such as maternal immune infection, obstetric complications, childhood trauma and cannabis exposure. It is postulated that epigenetic factors, as well as regulatory non-coding RNAs, mediate the effects of these environmental stressors. In this review, we explore the most well-known epigenetic marks, including DNA methylation and histone modification, along with emerging RNA mediators of epigenomic state, including miRNAs and lncRNAs, and discuss their collective potential for involvement in the pathophysiology of schizophrenia implicated through the postmortem analysis of brain tissue. Given that peripheral tissues, such as blood, saliva, and olfactory epithelium have the same genetic composition and are exposed to many of the same environmental exposures, we also examine some studies supporting the application of peripheral tissues for epigenomic biomarker discovery in schizophrenia. Finally, we provide some perspective on how these biomarkers may be utilized to capture a signature of past events that informs future treatment.
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Smigielski L, Jagannath V, Rössler W, Walitza S, Grünblatt E. Epigenetic mechanisms in schizophrenia and other psychotic disorders: a systematic review of empirical human findings. Mol Psychiatry 2020; 25:1718-1748. [PMID: 31907379 DOI: 10.1038/s41380-019-0601-3] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 11/05/2019] [Accepted: 11/07/2019] [Indexed: 12/26/2022]
Abstract
Schizophrenia and other psychotic disorders are highly debilitating psychiatric conditions that lack a clear etiology and exhibit polygenic inheritance underlain by pleiotropic genes. The prevailing explanation points to the interplay between predisposing genes and environmental exposure. Accumulated evidence suggests that epigenetic regulation of the genome may mediate dynamic gene-environment interactions at the molecular level by modulating the expression of psychiatric phenotypes through transcription factors. This systematic review summarizes the current knowledge linking schizophrenia and other psychotic disorders to epigenetics, based on PubMed and Web of Science database searches conducted according to the PRISMA guidelines. Three groups of mechanisms in case-control studies of human tissue (i.e., postmortem brain and bio-fluids) were considered: DNA methylation, histone modifications, and non-coding miRNAs. From the initial pool of 3,204 records, 152 studies met our inclusion criteria (11,815/11,528, 233/219, and 2,091/1,827 cases/controls for each group, respectively). Many of the findings revealed associations with epigenetic modulations of genes regulating neurotransmission, neurodevelopment, and immune function, as well as differential miRNA expression (e.g., upregulated miR-34a, miR-7, and miR-181b). Overall, actual evidence moderately supports an association between epigenetics and schizophrenia and other psychotic disorders. However, heterogeneous results and cross-tissue extrapolations call for future work. Integrating epigenetics into systems biology may critically enhance research on psychosis and thus our understanding of the disorder. This may have implications for psychiatry in risk stratification, early recognition, diagnostics, precision medicine, and other interventional approaches targeting epigenetic fingerprints.
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Affiliation(s)
- Lukasz Smigielski
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich, Switzerland. .,The Zurich Program for Sustainable Development of Mental Health Services (ZInEP), University Hospital of Psychiatry Zurich, Zurich, Switzerland.
| | - Vinita Jagannath
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich, Switzerland.,Merck Sharp & Dohme (MSD) R&D Innovation Centre, London, UK
| | - Wulf Rössler
- The Zurich Program for Sustainable Development of Mental Health Services (ZInEP), University Hospital of Psychiatry Zurich, Zurich, Switzerland.,Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Psychiatry, University of Zurich, Zurich, Switzerland.,Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin, Berlin, Germany.,Laboratory of Neuroscience, Institute of Psychiatry, Universidade de São Paulo, São Paulo, Brazil
| | - Susanne Walitza
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich, Switzerland.,The Zurich Program for Sustainable Development of Mental Health Services (ZInEP), University Hospital of Psychiatry Zurich, Zurich, Switzerland.,Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Edna Grünblatt
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich, Switzerland.,Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
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Ho NF, Tng JXJ, Wang M, Chen G, Subbaraju V, Shukor S, Ng DSX, Tan BL, Puang SJ, Kho SH, Siew RWE, Sin GL, Eu PW, Zhou J, Sng JCG, Sim K, Medalia A. Plasticity of DNA methylation, functional brain connectivity and efficiency in cognitive remediation for schizophrenia. J Psychiatr Res 2020; 126:122-133. [PMID: 32317108 DOI: 10.1016/j.jpsychires.2020.03.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 03/23/2020] [Accepted: 03/23/2020] [Indexed: 11/24/2022]
Abstract
Cognitive remediation (CR) is predicated on principles of neuroplasticity, but the actual molecular and neurocircuitry changes underlying cognitive change in individuals with impaired neuroplastic processes is poorly understood. The present study examined epigenetic-neurocircuitry-behavioral outcome measures in schizophrenia, before and after participating in a CR program that targeted higher-order cognitive functions. Outcome measures included DNA methylation of genes central to synaptic plasticity (CpG sites of Reelin promoter and BDNF promoter) from buccal swabs, resting-state functional brain connectivity and topological network efficiency, and global scores of a cognitive battery from 35 inpatients in a rehabilitative ward (18 CR, 17 non-CR) with similar premorbid IQ to 15 healthy controls. Baseline group differences between healthy controls and schizophrenia, group-by-time effects of CR in schizophrenia, and associations between the outcome measures were tested. Baseline functional connectivity abnormalities within the frontal, fronto-temporal and fronto-parietal regions, and trending decreases in global efficiency, but not DNA methylation, were found in schizophrenia; the frontal and fronto-temporal connectivity, and global efficiency correlated with global cognitive performance across all individuals. Notably, CR resulted in differential changes in Reelin promoter CpG methylation levels, altered within-frontal and fronto-temporal functional connectivity, increasing global efficiency and improving cognitive performance in schizophrenia, when compared to non-CR. In the CR inpatients, positive associations between the micro to macro measures: Reelin methylation changes, higher global efficiency and improving global cognitive performance were found. Present findings provide a neurobiological insight into potential CR-led epigenetics-neurocircuitry modifications driving cognitive plasticity.
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Affiliation(s)
- New Fei Ho
- Institute of Mental Health, Singapore; Duke-National University of Singapore Medical School, Singapore.
| | | | | | | | | | | | | | - Bhing-Leet Tan
- Institute of Mental Health, Singapore; Singapore Institute of Technology, Singapore
| | - Shu Juan Puang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Sok-Hong Kho
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Rachel Wan En Siew
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | | | - Juan Zhou
- Duke-National University of Singapore Medical School, Singapore; Center for Sleep and Cognition, Cognitive Neuroscience, Yong Loo Lin School of Medicine, National University of Singapore, SIngapore
| | - Judy Chia Ghee Sng
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Kang Sim
- Institute of Mental Health, Singapore
| | - Alice Medalia
- Columbia University College of Physicians and Surgeons, New York, USA
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Methylation of glucocorticoid receptor (NR3C1), BDNF and oxytocin receptor genes in association with childhood maltreatment in schizophrenia and schizoaffective disorder. Schizophr Res 2020; 216:529-531. [PMID: 31813807 DOI: 10.1016/j.schres.2019.11.050] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 11/14/2019] [Accepted: 11/26/2019] [Indexed: 11/22/2022]
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Gutierrez A, Corey-Bloom J, Thomas EA, Desplats P. Evaluation of Biochemical and Epigenetic Measures of Peripheral Brain-Derived Neurotrophic Factor (BDNF) as a Biomarker in Huntington's Disease Patients. Front Mol Neurosci 2020; 12:335. [PMID: 32038165 PMCID: PMC6989488 DOI: 10.3389/fnmol.2019.00335] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 12/27/2019] [Indexed: 12/17/2022] Open
Abstract
Huntington's disease (HD) is an autosomal-dominant neurodegenerative movement disorder that presents with prominent cognitive and psychiatric dysfunction. Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of HD, as well as other neurodegenerative and psychiatric disorders, and epigenetic alterations in the complex BDNF promoter have been associated with its deregulation in pathological conditions. BDNF has gained increased attention as a potential biomarker of disease; but currently, the conflicting results from measurements of BDNF in different biofluids difficult the assessment of its utility as a biomarker for HD. Here, we measured BDNF protein levels in plasma (n = 85) and saliva (n = 81) samples from premanifest and manifest HD patients and normal controls using ELISA assays. We further examined DNA methylation levels of BDNF promoter IV using DNA derived from whole blood of HD patients and healthy controls (n = 40) using pyrosequencing. BDNF protein levels were not significantly different in plasma samples across diagnostic groups. Plasma BDNF was significantly correlated with age in control subjects but not in HD patients, nor were significant gender effects observed. Similar to plasma, salivary BDNF was correlated with age only in control subjects, with no gender effects observed. Importantly, we detected significantly lower levels of salivary BDNF in premanifest and manifest HD patients compared to control subjects, with lower BDNF levels being observed in premanifest patients within a predicted 10 years to disease onset. Salivary and plasma BDNF levels were not significantly correlated with one another, suggesting different origins. DNA methylation at four out of the 12 CpG sites studied in promoter IV were significantly altered in HD patients in comparison to controls. Interestingly, methylation at three of these CpG sites was inversely correlated to the Hospital Anxiety and Depression Scale (HADS) scores. BDNF promoter methylation was not correlated with motor or cognitive scores in HD patients, and was not associated with sex or age in neither disease nor control groups. Conclusion: Our studies show that BDNF protein levels are decreased in saliva; and BDNF promoter methylation increased in blood in HD subjects when compared to controls. These findings suggest that salivary BDNF measures may represent an early marker of disease onset and DNA methylation at the BDNF promoter IV, could represent a biomarker of psychiatric symptoms in HD patients.
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Affiliation(s)
- Ashley Gutierrez
- Department of Neuroscience, School of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Jody Corey-Bloom
- Department of Neuroscience, School of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Elizabeth A. Thomas
- Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, United States
| | - Paula Desplats
- Department of Neuroscience, School of Medicine, University of California, San Diego, San Diego, CA, United States
- Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, United States
- Department of Pathology, School of Medicine, University of California, San Diego, San Diego, CA, United States
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BDNF genetic variants and methylation: effects on cognition in major depressive disorder. Transl Psychiatry 2019; 9:265. [PMID: 31636250 PMCID: PMC6803763 DOI: 10.1038/s41398-019-0601-8] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 06/29/2019] [Accepted: 07/30/2019] [Indexed: 02/07/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF) gene regulation has been linked to the pathophysiology of major depressive disorder (MDD). MDD patients show cognitive deficits, and altered BDNF regulation has a relevant role in neurocognitive functions. Our goal was to explore the association between BDNF genetic and epigenetic variations with neurocognitive performance in a group of MDD patients and healthy controls considering possible modulating factors. The sample included 134 subjects, 64 MDD patients, and 70 healthy controls. Clinical data, childhood maltreatment, and neurocognitive performance were assessed in all participants. Eleven single nucleotide polymorphisms (SNPs) and two promoter regions in the BDNF gene were selected for genotype and methylation analysis. The role of interactions between BDNF genetic and epigenetic variations with MDD diagnosis, sex, and Childhood Trauma Questionnaire (CTQ) scores was also explored. We observed significant associations between neurocognitive performance and two BDNF SNPs (rs908867 and rs925946), an effect that was significantly mediated by methylation values at specific promoter I sites. We identified significant associations between neurocognitive results and methylation status as well as its interactions with MDD diagnosis, sex, and CTQ scores. Our results support the hypothesis that BDNF gene SNPs and methylation status, as well as their interactions with modulating factors, can influence cognition. Further studies are required to confirm the effect of BDNF variations and cognitive function in larger samples.
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Wrigglesworth J, Ryan J, Vijayakumar N, Whittle S. Brain-derived neurotrophic factor DNA methylation mediates the association between neighborhood disadvantage and adolescent brain structure. Psychiatry Res Neuroimaging 2019; 285:51-57. [PMID: 30771753 DOI: 10.1016/j.pscychresns.2018.12.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 12/22/2018] [Accepted: 12/22/2018] [Indexed: 12/13/2022]
Abstract
Prior research indicates that socioeconomic disadvantage is associated with prefrontal cortical (PFC) development in childhood and adolescence, however the mechanisms of this link are unclear. This study investigated whether DNA methylation of the brain-derived neurotrophic factor (BDNF, which plays a key role in synaptic plasticity), mediated the association between neighborhood disadvantage and thickness of the PFC in adolescents. Neighborhood disadvantage was measured in 33 adolescents aged 12-13 years using the Socio-Economic Indexes for Areas. Buccal swabs, collected during mid-adolescence (aged 16-18 years), enabled BDNF DNA methylation of the widely studied exon IV promoter region to be measured. Cortical thickness was assessed during late-adolescence (aged 18-20 years) via T1-weighted magnetic resonance imaging (MRI). A significant negative association between disadvantage and BDNF DNA methylation at a specific site of the exon IV promoter was identified. Lower levels of methylation were also significantly associated with greater thickness of the lateral orbitofrontal cortex (lOFC), and right medial OFC. Lower levels of DNA methylation at this site also mediated associations between higher disadvantage and thinner bilateral lOFC thickness. These novel findings give insight into a potential biological mechanism that could further our understanding as to why brain development is affected by varying environmental exposures.
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Affiliation(s)
- Jo Wrigglesworth
- Melbourne Neuropsychiatry Center, Department of Psychiatry, The University of Melbourne and Melbourne Health, Parkville, Victoria, Australia; Disease Epigenetics, Murdoch Children's Research Institute, The University of Melbourne, Parkville, Victoria, Australia
| | - Joanne Ryan
- Disease Epigenetics, Murdoch Children's Research Institute, The University of Melbourne, Parkville, Victoria, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | | | - Sarah Whittle
- Melbourne Neuropsychiatry Center, Department of Psychiatry, The University of Melbourne and Melbourne Health, Parkville, Victoria, Australia; Melbourne School of Psychological Sciences, The University of Melbourne, Melbourne, Victoria, Australia.
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Föcking M, Doyle B, Munawar N, Dillon ET, Cotter D, Cagney G. Epigenetic Factors in Schizophrenia: Mechanisms and Experimental Approaches. MOLECULAR NEUROPSYCHIATRY 2019; 5:6-12. [PMID: 31019914 DOI: 10.1159/000495063] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 10/30/2018] [Indexed: 12/12/2022]
Abstract
Schizophrenia is a chronic mental disorder that is still poorly understood despite decades of study. Many factors have been found to contribute to the pathogenesis, including neurodevelopmental disturbance, genetic risk, and environmental insult, but no single root cause has emerged. While evidence from twin studies suggests a strong heritable component, few individual loci have been identified in genomewide screens, suggesting a role for epigenetic effects. Rather, large numbers of weakly acting loci may cumulatively increase disease risk, including several mapping to epigenetic pathways. In this review, we discuss mechanisms of epigenetic regulation and evidence for an epigenetic contribution to disease phenotype. We further describe the range of experimental tools currently available to study epigenetic effects associated with the disease.
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Affiliation(s)
- Melanie Föcking
- Department of Psychiatry, Royal College of Surgeons in Ireland (RCSI), Beaumont Hospital, Dublin, Ireland
| | - Benjamin Doyle
- Department of Psychiatry, Royal College of Surgeons in Ireland (RCSI), Beaumont Hospital, Dublin, Ireland
| | - Nayla Munawar
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Ireland
| | - Eugene T Dillon
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Ireland
| | - David Cotter
- Department of Psychiatry, Royal College of Surgeons in Ireland (RCSI), Beaumont Hospital, Dublin, Ireland
| | - Gerard Cagney
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Ireland
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Föcking M, Doyle B, Munawar N, Dillon E, Cotter D, Cagney G. Epigenetic Factors in Schizophrenia: Mechanisms and Experimental Approaches. MOLECULAR NEUROPSYCHIATRY 2019. [DOI: https://doi.org/10.1159/000495063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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The role of neurotrophins in psychopathology and cardiovascular diseases: psychosomatic connections. J Neural Transm (Vienna) 2019; 126:265-278. [PMID: 30767081 PMCID: PMC6449302 DOI: 10.1007/s00702-019-01973-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 01/16/2019] [Indexed: 12/18/2022]
Abstract
Cardiovascular (CV) diseases and mood disorders are common public health problems worldwide. Their connections are widely studied, and the role of neurotrophins (NTs) is already supposed in both conditions. However, data in the literature of clinical aspects are sometimes controversial and no reviews are available describing possible associations between CV risk and mood disorders based on NTs. The mostly studied NT is brain-derived neurotrophic factor (BDNF). Decreased level of BDNF is observed in depression and its connection to hypertension has also been demonstrated with affecting the arterial baroreceptors, renin–angiotensin system and endothelial nitric oxide synthase. BDNF was also found to be the predictor of CV outcome in different patient populations. Other types of human NT-s, such as nerve growth factor, neurotrophin 3 and neurotrophin 4 also seem to have both psychopathological and CV connections. Our aim was to overview the present knowledge in this area, demonstrating a new aspect of the associations between mood disorders and CV diseases through the mediation of NTs. These findings might enlighten new psychosomatic connections and suggest new therapeutic targets that are beneficial both in respect of mood disorders and CV pathology.
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Sarne V, Braunmueller S, Rakob L, Seeboeck R. The Relevance of Gender in Tumor-Influencing Epigenetic Traits. EPIGENOMES 2019; 3:epigenomes3010006. [PMID: 34991275 PMCID: PMC8594720 DOI: 10.3390/epigenomes3010006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 01/20/2019] [Accepted: 01/24/2019] [Indexed: 12/22/2022] Open
Abstract
Tumorigenesis as well as the molecular orchestration of cancer progression are very complex mechanisms that comprise numerous elements of influence and regulation. Today, many of the major concepts are well described and a basic understanding of a tumor's fine-tuning is given. Throughout the last decade epigenetics has been featured in cancer research and it is now clear that the underlying mechanisms, especially DNA and histone modifications, are important regulators of carcinogenesis and tumor progression. Another key regulator, which is well known but has been neglected in scientific approaches as well as molecular diagnostics and, consequently, treatment conceptualization for a long time, is the subtle influence patient gender has on molecular processes. Naturally, this is greatly based on hormonal differences, but from an epigenetic point of view, the diverse susceptibility to stress and environmental influences is of prime interest. In this review we present the current view on which and how epigenetic modifications, emphasizing DNA methylation, regulate various tumor diseases. It is our aim to elucidate gender and epigenetics and their interconnectedness, which will contribute to understanding of the prospect molecular orchestration of cancer in individual tumors.
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Amoli MM, Khatami F, Arzaghi SM, Enayati S, Nejatisafa AA. Over-expression of TGF-β1 gene in medication free Schizophrenia. Psychoneuroendocrinology 2019; 99:265-270. [PMID: 30389222 DOI: 10.1016/j.psyneuen.2018.10.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Revised: 10/13/2018] [Accepted: 10/14/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND PURPOSE Immunological pathways play a crucial role in developing and precipitating neuropsychiatric disorders. Although the exact pathogenesis of schizophrenia is unknown, the possible role of genetic and biomarker involvement of the immune system is gaining attention. Here we quantified the mRNA expression of cytokines as a key role player of the immune system from the peripheral blood mononuclear cells of patients with schizophrenia and healthy controls to identify the differentially expressed genes. METHODS Sixteen medication-free schizophrenia patients and 16 healthy subjects were enrolled in the current study. To investigate the desired expression level of mRNAs including TGF-β1, IL-1β, IL-23, TNF-α, NF-κB, and BDNF, quantitative real-time PCR was performed using specific oligonucleotide primers and the Applied Bio systems StepOne™ real time PCR system. DNA methylation was also analyzed through methylation-specific polymerase chain reaction (MSP). RESULTS TGF-β1 was significantly up-regulated in peripheral blood mononuclear cells of patients vs. healthy individuals (P value = 0.03). In addition, we found a significant correlation between the positive symptom scale and TGF-β1 gene overexpression (r = 0.536, P = 0.039). However, we did not observe any statistically significant differences for the methylation status of CpG Islands 1 and 2 between the patients and normal group. No statistical significance was found either for gene expression of IL-1β (P = 0.32), IL-23 (P = 0.12), TNF-α (P = 0.87), NF-κB (P = 0.07), and BDNF (P = 0.33). CONCLUSIONS Although the number of medication-free schizophrenia patients is extremely limited, our data highlighted the potential role of TGF-β1 as a regulatory cytokine in complex inflammatory mechanism involved in medication-free schizophrenia. In addition, we observed that increased level of TGF-β1 mRNA in this disease might not be under methylation as an epigenetic control element at the genomic level.
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Affiliation(s)
- Mahsa M Amoli
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Khatami
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Masoud Arzaghi
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Samaneh Enayati
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali-Akbar Nejatisafa
- Psychiatry & Psychology Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Ihara K, Fuchikami M, Hashizume M, Okada S, Kawai H, Obuchi S, Hirano H, Fujiwara Y, Hachisu M, Hongyong K, Morinobu S. The influence of aging on the methylation status of brain-derived neurotrophic factor gene in blood. Int J Geriatr Psychiatry 2018; 33:1312-1318. [PMID: 29953671 DOI: 10.1002/gps.4927] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 05/08/2018] [Indexed: 01/28/2023]
Abstract
OBJECTIVE Brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of psychiatric disorders in adults and elderly individuals, and as a result, the DNA methylation (DNAm) of the BDNF gene in peripheral tissues including blood has been extensively examined to develop a useful biomarker for psychiatric disorders. However, studies to date have not previously investigated the effect of age on DNAm of the BDNF gene in blood. In this context, we measured DNAm of 39 CpG units in the CpG island at the promoter of exon I of the BDNF gene. METHODS We analyzed genomic DNA from peripheral blood of 105 health Japanese women 20 to 80 years of age to identify aging-associated change in DNAm of the BDNF gene. In addition, we examined the relationship between total MMSE scores, numbers of stressful life events, and serum BDNF levels on DNAm of the BDNF gene. The DNAm rate at each CpG unit was measured using a MassArray® system (Agena Bioscience), and serum BDNF levels were measured by ELISA. RESULTS There was a significant correlation between DNAm and age in 13 CpGs. However, there was no significant correlation between DNAm and total MMSE scores, numbers of life events, or serum BDNF levels. CONCLUSION Despite the small number of subjects and the inclusion of only female subjects, our results suggest that DNAm of 13 CpGs of the BDNF gene may be an appropriate biomarker for aging and useful for predicting increased susceptibility to age-related psychiatric disorders.
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Affiliation(s)
- Kazushige Ihara
- Hirosaki University Graduate School of Medicine, Department of Social Medicine, Aomori, Japan
| | | | - Masahiro Hashizume
- Toho University Faculty of Medicine, Department of Psychosomatic Medicine, Tokyo, Japan
| | - Satoshi Okada
- Hiroshima University, Department of Psychiatry and Neurosciences, Division of Frontier Graduate School of Biomedical Sciences, Hiroshima, Japan
| | - Hisashi Kawai
- Tokyo Metropolitan Institute of Gerontology, Human Care Research Team, Tokyo, Japan
| | - Shuichi Obuchi
- Tokyo Metropolitan Institute of Gerontology, Human Care Research Team, Tokyo, Japan
| | - Hirohiko Hirano
- Tokyo Metropolitan Geriatric Hospital, Department of Dentistry, Tokyo, Japan
| | - Yoshinori Fujiwara
- Tokyo Metropolitan Institute of Gerontology, Research Team for Social Participation and Community Health, Tokyo, Japan
| | - Mitsugu Hachisu
- Showa University, Department of Pharmaceutical therapeutics, Division of Clinical Pharmacy, Pharmacy School, Tokyo, Japan
| | - Kim Hongyong
- Tokyo Metropolitan Institute of Gerontology, Research Team for Promoting Independence of the Elderly, Tokyo, Japan
| | - Shigeru Morinobu
- Kochi University, Department of Neuropsychiatry, Kochi Medical School, Nankoku, Japan.,Kibi International University, Department of Occupational Therapy, School of Health Science and Social Welfare, Takahashi, Japan
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BayesCCE: a Bayesian framework for estimating cell-type composition from DNA methylation without the need for methylation reference. Genome Biol 2018; 19:141. [PMID: 30241486 PMCID: PMC6151042 DOI: 10.1186/s13059-018-1513-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 08/20/2018] [Indexed: 11/10/2022] Open
Abstract
We introduce a Bayesian semi-supervised method for estimating cell counts from DNA methylation by leveraging an easily obtainable prior knowledge on the cell-type composition distribution of the studied tissue. We show mathematically and empirically that alternative methods which attempt to infer cell counts without methylation reference only capture linear combinations of cell counts rather than provide one component per cell type. Our approach allows the construction of components such that each component corresponds to a single cell type, and provides a new opportunity to investigate cell compositions in genomic studies of tissues for which it was not possible before.
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