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Ngo AL, Ahmad CM, Gharavi Alkhansari N, Nguyen L, Zhang H. Epigenetic Insights into Substance Use Disorder and Associated Psychiatric Conditions. Complex Psychiatry 2025; 11:12-36. [PMID: 40201238 PMCID: PMC11975344 DOI: 10.1159/000544912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 02/19/2025] [Indexed: 04/10/2025] Open
Abstract
Background Substance use disorder (SUD) is closely associated with epigenetic modifications that significantly impact mental health outcomes. Alcohol and drug misuse induce widespread changes in the epigenome and transcriptome of the central nervous system, disrupting critical processes such as reward signaling and emotional regulation. These alterations in epigenetic regulation and gene expression often persist even after substance cessation, potentially contributing to the onset or worsening of psychiatric conditions, including schizophrenia, depression, stress, and anxiety. Summary This review delves into key epigenetic mechanisms underlying SUD and its comorbid psychiatric disorders, with a focus on DNA methylation, histone modifications, and noncoding RNA regulation. Additionally, it examines the influence of environmental and biological factors on the epigenome and evaluates emerging epigenetic-based therapeutic strategies aimed at treating SUD and related psychiatric conditions. Key Messages Gaining a deeper understanding of the epigenetic mechanisms driving SUD and its associated psychiatric disorders is crucial for the development of effective therapeutic interventions. This review highlights the potential of epigenetic-based pharmacological strategies to mitigate the societal and personal burdens linked to SUD and its mental health complications.
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Affiliation(s)
- Ambrose Loc Ngo
- College of Medicine, Kansas City University, Kansas City, MO, USA
| | | | | | - Linda Nguyen
- College of Pharmacy, Western University, Pomona, CA, USA
| | - Huiping Zhang
- Department of Psychiatry, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
- Section of Biomedical Genetics, Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
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Arčan IŠ, Kouter K, Zupanc T, Paska AV. Epigenetics and suicide: investigating altered H3K14ac unveiled differential expression in ADORA2A, B4GALT2 and MMP14. Epigenomics 2024; 16:701-714. [PMID: 38545853 PMCID: PMC11318710 DOI: 10.2217/epi-2023-0351] [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: 10/06/2023] [Accepted: 03/15/2024] [Indexed: 06/14/2024] Open
Abstract
Background: Environmental factors make an important contribution to suicide. Histone tails are prone to different modifications, leading to changes of chromatin (de)condensation and consequently gene expression. Materials & methods: Level of H3K14ac was studied with chromatin immunoprecipitation followed by high-throughput DNA sequencing. Genes were further validated with RT-qPCR; using hippocampal tissue. Results: We showed lowered H3K14ac levels in individuals who died by suicide. The genes ADORA2A, B4GALT2 and MMP14 showed differential expression in individuals who died by suicide. Identified genetic and protein interactions among genes show interactions with suicide-related genes. Conclusion: Further investigations of histone modifications in association with DNA methylation and miRNA are needed to expand our knowledge of the genes that could significantly contribute to suicide.
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Affiliation(s)
- Iris Šalamon Arčan
- Institute of Biochemistry & Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Katarina Kouter
- Institute of Biochemistry & Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Institute of Microbiology & Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tomaž Zupanc
- Institute of Forensic Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Alja Videtič Paska
- Institute of Biochemistry & Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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3
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Coelho A, Lima-Bastos S, Gobira P, Lisboa S. Endocannabinoid signaling and epigenetics modifications in the neurobiology of stress-related disorders. Neuronal Signal 2023; 7:NS20220034. [PMID: 37520658 PMCID: PMC10372471 DOI: 10.1042/ns20220034] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 06/30/2023] [Accepted: 07/07/2023] [Indexed: 08/01/2023] Open
Abstract
Stress exposure is associated with psychiatric conditions, such as depression, anxiety, and post-traumatic stress disorder (PTSD). It is also a vulnerability factor to developing or reinstating substance use disorder. Stress causes several changes in the neuro-immune-endocrine axis, potentially resulting in prolonged dysfunction and diseases. Changes in several transmitters, including serotonin, dopamine, glutamate, gamma-aminobutyric acid (GABA), glucocorticoids, and cytokines, are associated with psychiatric disorders or behavioral alterations in preclinical studies. Complex and interacting mechanisms make it very difficult to understand the physiopathology of psychiatry conditions; therefore, studying regulatory mechanisms that impact these alterations is a good approach. In the last decades, the impact of stress on biology through epigenetic markers, which directly impact gene expression, is under intense investigation; these mechanisms are associated with behavioral alterations in animal models after stress or drug exposure, for example. The endocannabinoid (eCB) system modulates stress response, reward circuits, and other physiological functions, including hypothalamus-pituitary-adrenal axis activation and immune response. eCBs, for example, act retrogradely at presynaptic neurons, limiting the release of neurotransmitters, a mechanism implicated in the antidepressant and anxiolytic effects after stress. Epigenetic mechanisms can impact the expression of eCB system molecules, which in turn can regulate epigenetic mechanisms. This review will present evidence of how the eCB system and epigenetic mechanisms interact and the consequences of this interaction in modulating behavioral changes after stress exposure in preclinical studies or psychiatric conditions. Moreover, evidence that correlates the involvement of the eCB system and epigenetic mechanisms in drug abuse contexts will be discussed.
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Affiliation(s)
- Arthur A. Coelho
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Brazil
- Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil
| | - Sávio Lima-Bastos
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Brazil
- Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil
| | - Pedro H. Gobira
- Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil
| | - Sabrina F. Lisboa
- Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil
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Holtby AR, Hall TJ, McGivney BA, Han H, Murphy KJ, MacHugh DE, Katz LM, Hill EW. Integrative genomics analysis highlights functionally relevant genes for equine behaviour. Anim Genet 2023. [DOI: 10.1111/age.13320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 03/10/2023] [Accepted: 03/12/2023] [Indexed: 03/29/2023]
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Dwivedi Y, Shelton RC. Genomics in Treatment Development. ADVANCES IN NEUROBIOLOGY 2023; 30:363-385. [PMID: 36928858 DOI: 10.1007/978-3-031-21054-9_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/18/2023]
Abstract
The Human Genome Project mapped the 3 billion base pairs in the human genome, which ushered in a new generation of genomically focused treatment development. While this has been very successful in other areas, neuroscience has been largely devoid of such developments. This is in large part because there are very few neurological or mental health conditions that are related to single-gene variants. While developments in pharmacogenomics have been somewhat successful, the use of genetic information in practice has to do with drug metabolism and adverse reactions. Studies of drug metabolism related to genetic variations are an important part of drug development. However, outside of cancer biology, the actual translation of genomic information into novel therapies has been limited. Epigenetics, which relates in part to the effects of the environment on DNA, is a promising newer area of relevance to CNS disorders. The environment can induce chemical modifications of DNA (e.g., cytosine methylation), which can be induced by the environment and may represent either shorter- or longer-term changes. Given the importance of environmental influences on CNS disorders, epigenetics may identify important treatment targets in the future.
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Affiliation(s)
- Yogesh Dwivedi
- Department of Psychiatry and Behavioral Neurobiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Richard C Shelton
- Department of Psychiatry and Behavioral Neurobiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
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6
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Mirza S, Docherty AR, Bakian A, Coon H, Soares JC, Walss-Bass C, Fries GR. Genetics and epigenetics of self-injurious thoughts and behaviors: Systematic review of the suicide literature and methodological considerations. Am J Med Genet B Neuropsychiatr Genet 2022; 189:221-246. [PMID: 35975759 PMCID: PMC9900606 DOI: 10.1002/ajmg.b.32917] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 05/26/2022] [Accepted: 07/26/2022] [Indexed: 02/01/2023]
Abstract
Suicide is a multifaceted and poorly understood clinical outcome, and there is an urgent need to advance research on its phenomenology and etiology. Epidemiological studies have demonstrated that suicidal behavior is heritable, suggesting that genetic and epigenetic information may serve as biomarkers for suicide risk. Here we systematically review the literature on genetic and epigenetic alterations observed in phenotypes across the full range of self-injurious thoughts and behaviors (SITB). We included 577 studies focused on genome-wide and epigenome-wide associations, candidate genes (SNP and methylation), noncoding RNAs, and histones. Convergence of specific genes is limited across units of analysis, although pathway-based analyses do indicate nervous system development and function and immunity/inflammation as potential underlying mechanisms of SITB. We provide suggestions for future work on the genetic and epigenetic correlates of SITB with a specific focus on measurement issues.
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Affiliation(s)
- Salahudeen Mirza
- Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, (UTHealth), Houston, Texas, USA,Institute of Child Development, University of Minnesota, Minneapolis, Minnesota, USA
| | - Anna R. Docherty
- Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah, USA,Huntsman Mental Health Institute, Salt Lake City, Utah, USA,Department of Psychiatry, The Virginia Commonwealth University, Richmond, Virginia, USA
| | - Amanda Bakian
- Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah, USA,Huntsman Mental Health Institute, Salt Lake City, Utah, USA
| | - Hilary Coon
- Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah, USA,Huntsman Mental Health Institute, Salt Lake City, Utah, USA
| | - Jair C. Soares
- Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, (UTHealth), Houston, Texas, USA,Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA
| | - Consuelo Walss-Bass
- Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, (UTHealth), Houston, Texas, USA,Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA
| | - Gabriel R. Fries
- Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, (UTHealth), Houston, Texas, USA,Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA,Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA
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7
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Dada O, Qian J, Al-Chalabi N, Kolla NJ, Graff A, Zai C, Gerretsen P, De Luca V. Epigenetic studies in suicidal ideation and behavior. Psychiatr Genet 2021; 31:205-215. [PMID: 34694247 DOI: 10.1097/ypg.0000000000000298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Most psychiatric disorders are associated with an elevated risk of suicide. Suicidal behavior is the product of the interaction of many risk factors, such as genetics and environmental factors. Hence, epigenetics research may help to understand the mechanisms leading to suicidal ideation and behavior. This review will discuss epigenetic studies in both suicidal ideation and behavior. Epigenetic modifications are likely to be important in both suicidal ideation and behavior. Most of the reviewed studies found significant epigenetic modifications linked with suicidal behavior rather than ideation. Although sizable research has been carried out on this topic, most studies have been done on small-scale samples, and future research is required in larger samples with better clinical characterization of suicide phenotypes to investigate these epigenetic modifications further.
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8
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Kouter K, Videtic Paska A. 'Omics' of suicidal behaviour: A path to personalised psychiatry. World J Psychiatry 2021; 11:774-790. [PMID: 34733641 PMCID: PMC8546767 DOI: 10.5498/wjp.v11.i10.774] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 07/16/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Psychiatric disorders, including suicide, are complex disorders that are affected by many different risk factors. It has been estimated that genetic factors contribute up to 50% to suicide risk. As the candidate gene approach has not identified a gene or set of genes that can be defined as biomarkers for suicidal behaviour, much is expected from cutting edge technological approaches that can interrogate several hundred, or even millions, of biomarkers at a time. These include the '-omic' approaches, such as genomics, transcriptomics, epigenomics, proteomics and metabolomics. Indeed, these have revealed new candidate biomarkers associated with suicidal behaviour. The most interesting of these have been implicated in inflammation and immune responses, which have been revealed through different study approaches, from genome-wide single nucleotide studies and the micro-RNA transcriptome, to the proteome and metabolome. However, the massive amounts of data that are generated by the '-omic' technologies demand the use of powerful computational analysis, and also specifically trained personnel. In this regard, machine learning approaches are beginning to pave the way towards personalized psychiatry.
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Affiliation(s)
- Katarina Kouter
- Faculty of Medicine, Institute of Biochemistry and Molecular Genetics, University of Ljubljana, Ljubljana SI-1000, Slovenia
| | - Alja Videtic Paska
- Faculty of Medicine, Institute of Biochemistry and Molecular Genetics, University of Ljubljana, Ljubljana SI-1000, Slovenia
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9
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Ramos-Rosales DF, Vazquez-Alaniz F, Urtiz-Estrada N, Ramirez-Valles EG, Mendez-Hernádez EM, Salas-Leal AC, Barraza-Salas M. Epigenetic marks in suicide: a review. Psychiatr Genet 2021; 31:145-161. [PMID: 34412082 DOI: 10.1097/ypg.0000000000000297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Suicide is a complex phenomenon and a global public health problem that involves several biological factors that could contribute to the pathophysiology of suicide. There is evidence that epigenetic factors influence some psychiatric disorders, suggesting a predisposition to suicide or suicidal behavior. Here, we review studies of molecular mechanisms of suicide in an epigenetic perspective in the postmortem brain of suicide completers and peripheral blood cells of suicide attempters. Besides, we include studies of gene-specific DNA methylation, epigenome-wide association, histone modification, and interfering RNAs as epigenetic factors. This review provides an overview of the epigenetic mechanisms described in different biological systems related to suicide, contributing to an understanding of the genetic regulation in suicide. We conclude that epigenetic marks are potential biomarkers in suicide, and they could become attractive therapeutic targets due to their reversibility and importance in regulating gene expression.
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Affiliation(s)
| | - Fernando Vazquez-Alaniz
- Facultad de Ciencias Químicas, Universidad Juárez del Estado de Durango
- Hospital General 450. Servicios de Salud de Durango
| | | | | | - Edna M Mendez-Hernádez
- Instituto de Investigación Científica, Universidad Juárez del Estado de Durango, Durango, México
| | - Alma C Salas-Leal
- Instituto de Investigación Científica, Universidad Juárez del Estado de Durango, Durango, México
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10
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Aly J, Engmann O. The Way to a Human's Brain Goes Through Their Stomach: Dietary Factors in Major Depressive Disorder. Front Neurosci 2020; 14:582853. [PMID: 33364919 PMCID: PMC7750481 DOI: 10.3389/fnins.2020.582853] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 11/09/2020] [Indexed: 12/12/2022] Open
Abstract
Globally, more than 250 million people are affected by depression (major depressive disorder; MDD), a serious and debilitating mental disorder. Currently available treatment options can have substantial side effects and take weeks to be fully effective. Therefore, it is important to find safe alternatives, which act more rapidly and in a larger number of patients. While much research on MDD focuses on chronic stress as a main risk factor, we here make a point of exploring dietary factors as a somewhat overlooked, yet highly promising approach towards novel antidepressant pathways. Deficiencies in various groups of nutrients often occur in patients with mental disorders. These include vitamins, especially members of the B-complex (B6, B9, B12). Moreover, an imbalance of fatty acids, such as omega-3 and omega-6, or an insufficient supply with minerals, including magnesium and zinc, are related to MDD. While some of them are relevant for the synthesis of monoamines, others play a crucial role in inflammation, neuroprotection and the synthesis of growth factors. Evidence suggests that when deficiencies return to normal, changes in mood and behavior can be, at least in some cases, achieved. Furthermore, supplementation with dietary factors (so called "nutraceuticals") may improve MDD symptoms even in the absence of a deficiency. Non-vital dietary factors may affect MDD symptoms as well. For instance, the most commonly consumed psychostimulant caffeine may improve behavioral and molecular markers of MDD. The molecular structure of most dietary factors is well known. Hence, dietary factors may provide important molecular tools to study and potentially help treat MDD symptoms. Within this review, we will discuss the role of dietary factors in MDD risk and symptomology, and critically discuss how they might serve as auxiliary treatments or preventative options for MDD.
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Affiliation(s)
- Janine Aly
- Faculty of Medicine, Friedrich Schiller Universität, Jena, Germany
| | - Olivia Engmann
- Institute for Human Genetics, Jena University Hospital, Jena, Germany
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11
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Keverne J, Binder EB. A Review of epigenetics in psychiatry: focus on environmental risk factors. MED GENET-BERLIN 2020. [DOI: 10.1515/medgen-2020-2004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Abstract
Epigenetic modifications play a key role in development and cell type specificity. These modifications seem to be particularly critical for brain development, where mutations in epigenetic enzymes have been associated with neurodevelopmental disorders as well as with the function of post-mitotic neurons. Epigenetic modifications can be influenced by genetic and environmental factors, both known major risk factors for psychiatric disorders. Epigenetic modifications may thus be an important mediator of the effects of genetic and environmental risk factors on cell function.
This review summarizes the different types of epigenetic regulation and then focuses on the mechanisms transducing environmental signals, especially adverse life events that are major risk factors for psychiatric disorders, into lasting epigenetic changes. This is followed by examples of how the environment can induce epigenetic changes that relate to the risk of psychiatric disorders.
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Affiliation(s)
| | - Elisabeth B. Binder
- Dept. of Translational Research in Psychiatry , Max Planck Institute of Psychiatry , Kraepelinstr. 2-10 , Munich , Germany
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Abstract
The risk for major depression is both genetically and environmentally determined. It has been proposed that epigenetic mechanisms could mediate the lasting increases in depression risk following exposure to adverse life events and provide a mechanistic framework within which genetic and environmental factors can be integrated. Epigenetics refers to processes affecting gene expression and translation that do not involve changes in the DNA sequence and include DNA methylation (DNAm) and microRNAs (miRNAs) as well as histone modifications. Here we review evidence for a role of epigenetics in the pathogenesis of depression from studies investigating DNAm, miRNAs, and histone modifications using different tissues and various experimental designs. From these studies, a model emerges where underlying genetic and environmental risk factors, and interactions between the two, could drive aberrant epigenetic mechanisms targeting stress response pathways, neuronal plasticity, and other behaviorally relevant pathways that have been implicated in major depression.
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Affiliation(s)
- Signe Penner-Goeke
- Dept of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
| | - Elisabeth B Binder
- Dept of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
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Cheung S, Woo J, Maes MS, Zai CC. Suicide epigenetics, a review of recent progress. J Affect Disord 2020; 265:423-438. [PMID: 32090769 DOI: 10.1016/j.jad.2020.01.040] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 11/17/2019] [Accepted: 01/11/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Suicide results in over 800,000 deaths every year, making it a major public health concern worldwide. It is highly complex, with genetic and environmental influences. Epigenetic mechanisms, including DNA methylation, miRNA, and histone modifications, could explain the complex interplay of environmental risk factors with genetic risk factors in the emergence of suicidal behavior. METHODS Here, we review the literature on suicide epigenetics over the past 10 years. RESULTS There has been significant progress in the field of suicide epigenetics, with emerging findings in the brain-derived neurotrophic factor and hypothalamic-pituitary-adrenal axis genes. LIMITATIONS Studying patient subgroups is needed in order to extract more comparable and reproducible epigenetic findings in suicide. CONCLUSIONS It is crucial to consider suicidal patients or suicide victims' distal and proximal past history e.g., early-life adversity and psychiatric disorder in epigenetic studies of suicidality.
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Affiliation(s)
- Serina Cheung
- Neurogenetics Section, Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada
| | - Julia Woo
- Neurogenetics Section, Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada; Faculty of Medicine, University of Toronto, Canada
| | - Miriam S Maes
- Neurogenetics Section, Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada
| | - Clement C Zai
- Neurogenetics Section, Tanenbaum Centre for Pharmacogenetics, Molecular Brain Science, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada; Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Canada; Institute of Medical Science, University of Toronto, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Canada; Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
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Policicchio S, Washer S, Viana J, Iatrou A, Burrage J, Hannon E, Turecki G, Kaminsky Z, Mill J, Dempster EL, Murphy TM. Genome-wide DNA methylation meta-analysis in the brains of suicide completers. Transl Psychiatry 2020; 10:69. [PMID: 32075955 PMCID: PMC7031296 DOI: 10.1038/s41398-020-0752-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/09/2020] [Accepted: 01/30/2020] [Indexed: 02/06/2023] Open
Abstract
Suicide is the second leading cause of death globally among young people representing a significant global health burden. Although the molecular correlates of suicide remains poorly understood, it has been hypothesised that epigenomic processes may play a role. The objective of this study was to identify suicide-associated DNA methylation changes in the human brain by utilising previously published and unpublished methylomic datasets. We analysed prefrontal cortex (PFC, n = 211) and cerebellum (CER, n = 114) DNA methylation profiles from suicide completers and non-psychiatric, sudden-death controls, meta-analysing data from independent cohorts for each brain region separately. We report evidence for altered DNA methylation at several genetic loci in suicide cases compared to controls in both brain regions with suicide-associated differentially methylated positions enriched among functional pathways relevant to psychiatric phenotypes and suicidality, including nervous system development (PFC) and regulation of long-term synaptic depression (CER). In addition, we examined the functional consequences of variable DNA methylation within a PFC suicide-associated differentially methylated region (PSORS1C3 DMR) using a dual luciferase assay and examined expression of nearby genes. DNA methylation within this region was associated with decreased expression of firefly luciferase but was not associated with expression of nearby genes, PSORS1C3 and POU5F1. Our data suggest that suicide is associated with DNA methylation, offering novel insights into the molecular pathology associated with suicidality.
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Affiliation(s)
- Stefania Policicchio
- grid.8391.30000 0004 1936 8024University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Sam Washer
- grid.8391.30000 0004 1936 8024University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Joana Viana
- grid.8391.30000 0004 1936 8024University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Artemis Iatrou
- grid.240684.c0000 0001 0705 3621Rush Alzheimer’s Neurodisease Center, Rush University Medical Center, 600 South Paulina Street, Chicago, IL 60612 USA
| | - Joe Burrage
- grid.8391.30000 0004 1936 8024University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Eilis Hannon
- grid.8391.30000 0004 1936 8024University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Gustavo Turecki
- grid.14709.3b0000 0004 1936 8649Douglas Institute, Department of Psychiatry, McGill University, Verdun, QC H4H 1R3 Canada
| | - Zachary Kaminsky
- grid.21107.350000 0001 2171 9311Department of Psychiatry, School of Medicine, Johns Hopkins University, Baltimore, MD USA ,grid.21107.350000 0001 2171 9311Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA
| | - Jonathan Mill
- grid.8391.30000 0004 1936 8024University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Emma L. Dempster
- grid.8391.30000 0004 1936 8024University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Therese M. Murphy
- grid.8391.30000 0004 1936 8024University of Exeter Medical School, University of Exeter, Exeter, UK ,grid.497880.aSchool of Biological and Health Sciences, Technological University Dublin, City Campus, Dublin, 2 Ireland
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Mustafin RN, Kazantseva AV, Enikeeva RF, Davydova YD, Malykh SB, Viktorov VV, Khusnutdinova EK. Epigenetics of suicidal behavior. Vavilovskii Zhurnal Genet Selektsii 2019. [DOI: 10.18699/vj19.531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Suicide is the second leading cause of death among young people and therefore being a serious global problem worldwide. The study of genetic and epigenetic factors in the development of suicidal behavior plays an important role in the development of advanced methods of diagnosis and treatment of this pathology. The role of hereditary factors in the development of suicidal behavior is estimated at 30–55 %, with a pronounced comorbidity with other psychopathologies. The study of genetic liability to suicidal behavior is based on molecular-genetic methods including association and linkage analyses, chip gene expression arrays, and genome-wide association studies. Published data identified multiple genes including those involved in the functioning of serotonergic (SLC6A4, TPH, 5-HT1A), hypothalamic-pituitary-adrenal systems (FKBP5) and polyamines (SAT and OATL1) associated with suicidal behavior. However, the diversity of interacting genetic loci complicates the interpretation of the development of a complex phenotype of pathology and prevents the association from being detected. To solve this problem and interpret the missing relationship between the environment and the genome, promising results were obtained from a study of epigenetic factors, which affected the expression of a number of candidate genes involved in brain functioning in suicidal behavior. The analysis of a brain obtained from suicide victims, representing a unique tool for the analysis of modified genomic processes, revealed a wide range of reprogramming patterns of DNA methylation in promoters of the genes of polyamine (OAZ1, OAZ2, AMD1, ARG2, SKA2), serotonergic (SLC6A4) and GABAergic (GABRA1) systems, HPA-axis (GR, NR3C1), tyrosine kinase (TrkB) receptors, brain-derived neurotrophic factor (BDNF). The role of histone modifications in distinct genes (Cx30, Cx43, TrkB.T1) and the expression of specific long noncoding RNAs and microRNAs in the development of suicidal behavior, which is promising for the development of diagnostic algorithms and target therapy, is discussed.
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Affiliation(s)
- R. N. Mustafin
- Bashkir State Medical University;
Bashkir State University
| | - A. V. Kazantseva
- Institute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre, RAS
| | - R. F. Enikeeva
- Bashkir State University;
Institute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre, RAS
| | - Yu. D. Davydova
- Institute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre, RAS
| | - S. B. Malykh
- Psychological Institute of the Russian Academy of Education
| | | | - E. K. Khusnutdinova
- Bashkir State Medical University;
Bashkir State University;
Institute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre, RAS
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González-Castro TB, Tovilla-Zárate CA, Genis-Mendoza AD, Juárez-Rojop IE, Nicolini H, López-Narváez ML, Martínez-Magaña JJ. Identification of gene ontology and pathways implicated in suicide behavior: Systematic review and enrichment analysis of GWAS studies. Am J Med Genet B Neuropsychiatr Genet 2019; 180:320-329. [PMID: 31045331 DOI: 10.1002/ajmg.b.32731] [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: 09/11/2018] [Revised: 04/03/2019] [Accepted: 04/16/2019] [Indexed: 12/14/2022]
Abstract
Multiple large-scale studies such as genome-wide association studies (GWAS) have been performed to identify genetic contributors to suicidal behaviors (SB). We aimed to summarize and analyze the information obtained in SB GWAS, to explore the biological process gene ontology (GO) of genes associated with SB from GWAS, and to determine the possible implications of the genes associated with SB in Kyoto encyclopedias of genes and genomes (KEGG) biological pathways. The articles included in the analysis were obtained from PubMed and Scopus databases. Enrichment analyses were performed in Enrichr to evaluate the KEGG pathways and GO of the genes associated with SB of GWAS. The findings of biological process GO analysis showed 924 GO involved in genes related with SB; of those, the regulation of glucose import in response to insulin stimulus, regulation of protein localization to plasma membrane, positive regulation of endopeptidase activity, heterotypic cell-cell adhesion, regulation of cardiac muscle cell contraction, positive regulation of protein localization to plasma membrane, and positive regulation of protein localization to cell periphery biological process GO showed significant statistical association. Furthermore, we obtained 130 KEGG pathways involved in genes related with SB, which Aldosterone synthesis and secretion, Rap1 signaling pathway and arrhythmogenic right ventricular cardiomyopathy pathways showed a significant statistical association. These findings give a better perspective of the biological participation of genes associated with SB, which will be important to perform adequate strategies to prevent and treat SB.
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Affiliation(s)
- Thelma B González-Castro
- Multidisciplinary Academic Division of Jalpa de Méndez, Juárez Autonomous University of Tabasco, Jalpa de Méndez, Tabasco, Mexico.,Multidisciplinary Academic Division of Health Sciences, Juárez Autonomous University of Tabasco, Villahermosa, Tabasco, Mexico
| | - Carlos A Tovilla-Zárate
- Multidisciplinary Academic Division of Comalcalco, Juárez Autonomous University of Tabasco, Comalcalco, Tabasco, Mexico
| | - Alma D Genis-Mendoza
- Secretary of Health, National Institute of Genomic Medicine (INMEGEN), City of Mexico, Mexico.,Secretary of Health, Children's Psychiatric Hospital "Dr. Juan N. Navarro", City of Mexico, Mexico
| | - Isela E Juárez-Rojop
- Multidisciplinary Academic Division of Comalcalco, Juárez Autonomous University of Tabasco, Comalcalco, Tabasco, Mexico
| | - Humberto Nicolini
- Secretary of Health, National Institute of Genomic Medicine (INMEGEN), City of Mexico, Mexico.,Secretary of Health, Children's Psychiatric Hospital "Dr. Juan N. Navarro", City of Mexico, Mexico
| | | | - José J Martínez-Magaña
- Secretary of Health, National Institute of Genomic Medicine (INMEGEN), City of Mexico, Mexico
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Sandusky-Beltran LA, Kovalenko A, Ma C, Calahatian JIT, Placides DS, Watler MD, Hunt JB, Darling AL, Baker JD, Blair LJ, Martin MD, Fontaine SN, Dickey CA, Lussier AL, Weeber EJ, Selenica MLB, Nash KR, Gordon MN, Morgan D, Lee DC. Spermidine/spermine-N 1-acetyltransferase ablation impacts tauopathy-induced polyamine stress response. Alzheimers Res Ther 2019; 11:58. [PMID: 31253191 PMCID: PMC6599347 DOI: 10.1186/s13195-019-0507-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 05/21/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Tau stabilizes microtubules; however, in Alzheimer's disease (AD) and tauopathies, tau becomes hyperphosphorylated, aggregates, and results in neuronal death. Our group recently uncovered a unique interaction between polyamine metabolism and tau fate. Polyamines exert an array of physiological effects that support neuronal function and cognitive processing. Specific stimuli can elicit a polyamine stress response (PSR), resulting in altered central polyamine homeostasis. Evidence suggests that elevations in polyamines following a short-term stressor are beneficial; however, persistent stress and subsequent PSR activation may lead to maladaptive polyamine dysregulation, which is observed in AD, and may contribute to neuropathology and disease progression. METHODS Male and female mice harboring tau P301L mutation (rTg4510) were examined for a tau-induced central polyamine stress response (tau-PSR). The direct effect of tau-PSR byproducts on tau fibrillization and oligomerization were measured using a thioflavin T assay and a N2a split superfolder GFP-Tau (N2a-ssGT) cell line, respectively. To therapeutically target the tau-PSR, we bilaterally injected caspase 3-cleaved tau truncated at aspartate 421 (AAV9 Tau ΔD421) into the hippocampus and cortex of spermidine/spermine-N1-acetyltransferase (SSAT), a key regulator of the tau-PSR, knock out (SSAT-/-), and wild type littermates, and the effects on tau neuropathology, polyamine dysregulation, and behavior were measured. Lastly, cellular models were employed to further examine how SSAT repression impacted tau biology. RESULTS Tau induced a unique tau-PSR signature in rTg4510 mice, notably in the accumulation of acetylated spermidine. In vitro, higher-order polyamines prevented tau fibrillization but acetylated spermidine failed to mimic this effect and even promoted fibrillization and oligomerization. AAV9 Tau ΔD421 also elicited a unique tau-PSR in vivo, and targeted disruption of SSAT prevented the accumulation of acetylated polyamines and impacted several tau phospho-epitopes. Interestingly, SSAT knockout mice presented with altered behavior in the rotarod task, the elevated plus maze, and marble burying task, thus highlighting the impact of polyamine homeostasis within the brain. CONCLUSION These data represent a novel paradigm linking tau pathology and polyamine dysfunction and that targeting specific arms within the polyamine pathway may serve as new targets to mitigate certain components of the tau phenotype.
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Affiliation(s)
- Leslie A. Sandusky-Beltran
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South Florida, 4001 E. Fletcher Ave, Tampa, FL 33613 USA
- 0000 0004 1936 8753grid.137628.9Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, 1 Park Avenue, New York, NY 10016 USA
| | - Andrii Kovalenko
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South Florida, 4001 E. Fletcher Ave, Tampa, FL 33613 USA
| | - Chao Ma
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33613 USA
| | - John Ivan T. Calahatian
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South Florida, 4001 E. Fletcher Ave, Tampa, FL 33613 USA
| | - Devon S. Placides
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South Florida, 4001 E. Fletcher Ave, Tampa, FL 33613 USA
| | - Mallory D. Watler
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South Florida, 4001 E. Fletcher Ave, Tampa, FL 33613 USA
| | - Jerry B. Hunt
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South Florida, 4001 E. Fletcher Ave, Tampa, FL 33613 USA
| | - April L. Darling
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Molecular Medicine, University of South Florida, Tampa, FL 33613 USA
| | - Jeremy D. Baker
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Molecular Medicine, University of South Florida, Tampa, FL 33613 USA
| | - Laura J. Blair
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Molecular Medicine, University of South Florida, Tampa, FL 33613 USA
| | - Mackenzie D. Martin
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Molecular Medicine, University of South Florida, Tampa, FL 33613 USA
| | - Sarah N. Fontaine
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Molecular Medicine, University of South Florida, Tampa, FL 33613 USA
| | - Chad A. Dickey
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Molecular Medicine, University of South Florida, Tampa, FL 33613 USA
| | - April L. Lussier
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33613 USA
| | - Edwin J. Weeber
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33613 USA
| | - Maj-Linda B. Selenica
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South Florida, 4001 E. Fletcher Ave, Tampa, FL 33613 USA
| | - Kevin R. Nash
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33613 USA
| | - Marcia N. Gordon
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33613 USA
- 0000 0001 2150 1785grid.17088.36Department of Translational Science & Molecular Medicine, Michigan State University, 400 Monroe Ave NW, Grand Rapids, MI 49503 USA
| | - Dave Morgan
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33613 USA
- 0000 0001 2150 1785grid.17088.36Department of Translational Science & Molecular Medicine, Michigan State University, 400 Monroe Ave NW, Grand Rapids, MI 49503 USA
| | - Daniel C. Lee
- 0000 0001 2353 285Xgrid.170693.aByrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South Florida, 4001 E. Fletcher Ave, Tampa, FL 33613 USA
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Chen GG, Almeida D, Fiori L, Turecki G. Evidence of Reduced Agmatine Concentrations in the Cerebral Cortex of Suicides. Int J Neuropsychopharmacol 2018; 21:895-900. [PMID: 29986038 PMCID: PMC6165952 DOI: 10.1093/ijnp/pyy058] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 06/29/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The polyamines are a group of ubiquitous low-molecular-weight aliphatic molecules that play an essential role in various physiological functions of the mammalian CNS. Previous literature has indicated alterations in the expression of polyamine-related genes in the brains of individuals who died by suicide, including downregulation of spermidine/spermine N1-acetyltransferase, a key enzyme involved in polyamine catabolism. One such polyamine, agmatine, has been shown to act as an antidepressant in animal models of depressive-like behavior. However, agmatine concentrations have not been explored in postmortem human brain of individuals who died by suicide. METHODS To measure agmatine in postmortem human brain tissue, we employed our previously published high-resolution capillary gas chromatography in combination with mass spectrometry method. Using this method, we analyzed agmatine levels in a total of 120 tissue samples from Brodmann areas 4, 11, and 44 of 40 male subjects comprising controls (n=13), individuals who died by suicide and met criteria for major depressive disorder (n=14), and subjects who died by suicide and did not meet criteria for major depressive disorder (n=13). RESULTS Agmatine fell within the expected nanomolar range and was significantly reduced in the cortex of suicides, irrespective of meeting criteria for major depressive disorder compared with controls. CONCLUSIONS This is the first gas chromatography-mass spectrometry study to analyze agmatine concentrations in human postmortem brain of individuals who died by suicide. These results add to our mechanistic understanding of the role that the polyamine stress response pathway may play in the neurobiology of major depression and/or suicide.
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Affiliation(s)
- Gary G Chen
- McGill Group for Suicide Studies, Douglas Hospital Research Center, Verdun, QC, Canada
| | - Daniel Almeida
- McGill Group for Suicide Studies, Douglas Hospital Research Center, Verdun, QC, Canada
| | - Laura Fiori
- McGill Group for Suicide Studies, Douglas Hospital Research Center, Verdun, QC, Canada
| | - Gustavo Turecki
- McGill Group for Suicide Studies, Douglas Hospital Research Center, Verdun, QC, Canada,Department of Psychiatry, McGill University, Montreal, QC, Canada,Correspondence: Gustavo Turecki, MD, PhD, Douglas Mental Health University Institute, Frank B Common Pavilion, Room F-3125, 6875 LaSalle Boulevard, Montreal, Quebec, H4H 1R3 ()
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19
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Differential exosomal microRNA profile in the serum of a patient with depression. THE EUROPEAN JOURNAL OF PSYCHIATRY 2018. [DOI: 10.1016/j.ejpsy.2017.10.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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20
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Caraci F, Calabrese F, Molteni R, Bartova L, Dold M, Leggio GM, Fabbri C, Mendlewicz J, Racagni G, Kasper S, Riva MA, Drago F. International Union of Basic and Clinical Pharmacology CIV: The Neurobiology of Treatment-resistant Depression: From Antidepressant Classifications to Novel Pharmacological Targets. Pharmacol Rev 2018; 70:475-504. [PMID: 29884653 DOI: 10.1124/pr.117.014977] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Currently available antidepressants are effective for most patients, although around 30% are considered treatment resistant (TRD), a condition that is associated with a significant impairment of cognitive function and poor quality of life. In this respect, the identification of the molecular mechanisms contributing to TRD represents an essential step for the design of novel and more efficacious drugs able to modify the clinical course of this disorder and increase remission rates in clinical practice. New insights into the neurobiology of TRD have shed light on the role of a number of different mechanisms, including the glutamatergic system, immune/inflammatory systems, neurotrophin function, and epigenetics. Advances in drug discovery processes in TRD have also influenced the classification of antidepressant drugs and novel classifications are available, such as the neuroscience-based nomenclature that can incorporate such advances in drug development for TRD. This review aims to provide an up-to-date description of key mechanisms in TRD and describe current therapeutic strategies for TRD before examining novel approaches that may ultimately address important neurobiological mechanisms not targeted by currently available antidepressants. All in all, we suggest that drug targeting different neurobiological systems should be able to restore normal function but must also promote resilience to reduce the long-term vulnerability to recurrent depressive episodes.
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Affiliation(s)
- F Caraci
- Departments of Drug Sciences (F.Car.) and Biomedical and Biotechnological Sciences, School of Medicine (G.M.L., F.D.), University of Catania, Catania, Italy; Oasi-Research-Institute-IRCCS, Troina, Italy (F.Car.); Departments of Pharmacological and Biomolecular Sciences (F.Cal., G.R., M.A.R.) and Medical Biotechnology and Translational Medicine (R.M.), Università degli Studi di Milano, Milan, Italy; Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (L.B., M.D., S.K.); Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy (C.F.); and School of Medicine, Universite' Libre de Bruxelles, Bruxelles, Belgium (J.M.)
| | - F Calabrese
- Departments of Drug Sciences (F.Car.) and Biomedical and Biotechnological Sciences, School of Medicine (G.M.L., F.D.), University of Catania, Catania, Italy; Oasi-Research-Institute-IRCCS, Troina, Italy (F.Car.); Departments of Pharmacological and Biomolecular Sciences (F.Cal., G.R., M.A.R.) and Medical Biotechnology and Translational Medicine (R.M.), Università degli Studi di Milano, Milan, Italy; Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (L.B., M.D., S.K.); Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy (C.F.); and School of Medicine, Universite' Libre de Bruxelles, Bruxelles, Belgium (J.M.)
| | - R Molteni
- Departments of Drug Sciences (F.Car.) and Biomedical and Biotechnological Sciences, School of Medicine (G.M.L., F.D.), University of Catania, Catania, Italy; Oasi-Research-Institute-IRCCS, Troina, Italy (F.Car.); Departments of Pharmacological and Biomolecular Sciences (F.Cal., G.R., M.A.R.) and Medical Biotechnology and Translational Medicine (R.M.), Università degli Studi di Milano, Milan, Italy; Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (L.B., M.D., S.K.); Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy (C.F.); and School of Medicine, Universite' Libre de Bruxelles, Bruxelles, Belgium (J.M.)
| | - L Bartova
- Departments of Drug Sciences (F.Car.) and Biomedical and Biotechnological Sciences, School of Medicine (G.M.L., F.D.), University of Catania, Catania, Italy; Oasi-Research-Institute-IRCCS, Troina, Italy (F.Car.); Departments of Pharmacological and Biomolecular Sciences (F.Cal., G.R., M.A.R.) and Medical Biotechnology and Translational Medicine (R.M.), Università degli Studi di Milano, Milan, Italy; Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (L.B., M.D., S.K.); Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy (C.F.); and School of Medicine, Universite' Libre de Bruxelles, Bruxelles, Belgium (J.M.)
| | - M Dold
- Departments of Drug Sciences (F.Car.) and Biomedical and Biotechnological Sciences, School of Medicine (G.M.L., F.D.), University of Catania, Catania, Italy; Oasi-Research-Institute-IRCCS, Troina, Italy (F.Car.); Departments of Pharmacological and Biomolecular Sciences (F.Cal., G.R., M.A.R.) and Medical Biotechnology and Translational Medicine (R.M.), Università degli Studi di Milano, Milan, Italy; Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (L.B., M.D., S.K.); Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy (C.F.); and School of Medicine, Universite' Libre de Bruxelles, Bruxelles, Belgium (J.M.)
| | - G M Leggio
- Departments of Drug Sciences (F.Car.) and Biomedical and Biotechnological Sciences, School of Medicine (G.M.L., F.D.), University of Catania, Catania, Italy; Oasi-Research-Institute-IRCCS, Troina, Italy (F.Car.); Departments of Pharmacological and Biomolecular Sciences (F.Cal., G.R., M.A.R.) and Medical Biotechnology and Translational Medicine (R.M.), Università degli Studi di Milano, Milan, Italy; Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (L.B., M.D., S.K.); Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy (C.F.); and School of Medicine, Universite' Libre de Bruxelles, Bruxelles, Belgium (J.M.)
| | - C Fabbri
- Departments of Drug Sciences (F.Car.) and Biomedical and Biotechnological Sciences, School of Medicine (G.M.L., F.D.), University of Catania, Catania, Italy; Oasi-Research-Institute-IRCCS, Troina, Italy (F.Car.); Departments of Pharmacological and Biomolecular Sciences (F.Cal., G.R., M.A.R.) and Medical Biotechnology and Translational Medicine (R.M.), Università degli Studi di Milano, Milan, Italy; Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (L.B., M.D., S.K.); Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy (C.F.); and School of Medicine, Universite' Libre de Bruxelles, Bruxelles, Belgium (J.M.)
| | - J Mendlewicz
- Departments of Drug Sciences (F.Car.) and Biomedical and Biotechnological Sciences, School of Medicine (G.M.L., F.D.), University of Catania, Catania, Italy; Oasi-Research-Institute-IRCCS, Troina, Italy (F.Car.); Departments of Pharmacological and Biomolecular Sciences (F.Cal., G.R., M.A.R.) and Medical Biotechnology and Translational Medicine (R.M.), Università degli Studi di Milano, Milan, Italy; Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (L.B., M.D., S.K.); Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy (C.F.); and School of Medicine, Universite' Libre de Bruxelles, Bruxelles, Belgium (J.M.)
| | - G Racagni
- Departments of Drug Sciences (F.Car.) and Biomedical and Biotechnological Sciences, School of Medicine (G.M.L., F.D.), University of Catania, Catania, Italy; Oasi-Research-Institute-IRCCS, Troina, Italy (F.Car.); Departments of Pharmacological and Biomolecular Sciences (F.Cal., G.R., M.A.R.) and Medical Biotechnology and Translational Medicine (R.M.), Università degli Studi di Milano, Milan, Italy; Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (L.B., M.D., S.K.); Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy (C.F.); and School of Medicine, Universite' Libre de Bruxelles, Bruxelles, Belgium (J.M.)
| | - S Kasper
- Departments of Drug Sciences (F.Car.) and Biomedical and Biotechnological Sciences, School of Medicine (G.M.L., F.D.), University of Catania, Catania, Italy; Oasi-Research-Institute-IRCCS, Troina, Italy (F.Car.); Departments of Pharmacological and Biomolecular Sciences (F.Cal., G.R., M.A.R.) and Medical Biotechnology and Translational Medicine (R.M.), Università degli Studi di Milano, Milan, Italy; Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (L.B., M.D., S.K.); Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy (C.F.); and School of Medicine, Universite' Libre de Bruxelles, Bruxelles, Belgium (J.M.)
| | - M A Riva
- Departments of Drug Sciences (F.Car.) and Biomedical and Biotechnological Sciences, School of Medicine (G.M.L., F.D.), University of Catania, Catania, Italy; Oasi-Research-Institute-IRCCS, Troina, Italy (F.Car.); Departments of Pharmacological and Biomolecular Sciences (F.Cal., G.R., M.A.R.) and Medical Biotechnology and Translational Medicine (R.M.), Università degli Studi di Milano, Milan, Italy; Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (L.B., M.D., S.K.); Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy (C.F.); and School of Medicine, Universite' Libre de Bruxelles, Bruxelles, Belgium (J.M.)
| | - F Drago
- Departments of Drug Sciences (F.Car.) and Biomedical and Biotechnological Sciences, School of Medicine (G.M.L., F.D.), University of Catania, Catania, Italy; Oasi-Research-Institute-IRCCS, Troina, Italy (F.Car.); Departments of Pharmacological and Biomolecular Sciences (F.Cal., G.R., M.A.R.) and Medical Biotechnology and Translational Medicine (R.M.), Università degli Studi di Milano, Milan, Italy; Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria (L.B., M.D., S.K.); Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy (C.F.); and School of Medicine, Universite' Libre de Bruxelles, Bruxelles, Belgium (J.M.)
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Roy B, Dwivedi Y. Understanding the Neuroepigenetic Constituents of Suicide Brain. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2018; 157:233-262. [PMID: 29933952 DOI: 10.1016/bs.pmbts.2018.01.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Stressful life incidents often cause a predisposition for developing mental disorders such as major depressive disorder (MDD). Impaired neurocognitive and neuro-vegetative functions of the central nervous system are the hallmarks of this mental illness. Blunted responses from emotionally salient regions of the brain including cortex, hippocampus, and amygdala have been associated with MDD-related behavioral changes. Moreover, improper signal processing and neuronal atrophy were held responsible for the overall dysfunctionality of these vulnerable regions in the MDD brain. The prevalence of genetic susceptibility along with adverse environmental stimuli often makes the situation worse for MDD patients, leading to an increased risk of suicidal behavior and eventually death by suicide. Despite considerable efforts to understand the complex neurobiology associated with MDD and suicidal behavior, their pathological determinants remain mostly elusive. Recent research, however, has shown that epigenetic perturbations have a formidable impact on the etiopathogenesis of MDD. Understanding the neuroepigenetic nature of this mental disorder may provide opportunities to devise more effective treatment strategies. Moreover, this can potentially lead to identifying predictive biomarkers associated with suicide risk. The present chapter critically reviews studies pertaining to epigenetic signatures of MDD and suicide brain.
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Affiliation(s)
- Bhaskar Roy
- University of Alabama at Birmingham, Birmingham, AL, United States
| | - Yogesh Dwivedi
- University of Alabama at Birmingham, Birmingham, AL, United States.
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Lutz PE, Mechawar N, Turecki G. Neuropathology of suicide: recent findings and future directions. Mol Psychiatry 2017; 22:1395-1412. [PMID: 28696430 DOI: 10.1038/mp.2017.141] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 05/21/2017] [Accepted: 05/26/2017] [Indexed: 12/11/2022]
Abstract
Suicide is a major public health concern and a leading cause of death in most societies. Suicidal behaviour is complex and heterogeneous, likely resulting from several causes. It associates with multiple factors, including psychopathology, personality traits, early-life adversity and stressful life events, among others. Over the past decades, studies in fields ranging from neuroanatomy, genetics and molecular psychiatry have led to a model whereby behavioural dysregulation, including suicidal behaviour (SB), develops as a function of biological adaptations in key brain systems. More recently, the unravelling of the unique epigenetic processes that occur in the brain has opened promising avenues in suicide research. The present review explores the various facets of the current knowledge on suicidality and discusses how the rapidly evolving field of neurobehavioural epigenetics may fuel our ability to understand, and potentially prevent, SB.
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Affiliation(s)
- P-E Lutz
- McGill Group for Suicide Studies, McGill University, Douglas Mental Health University Institute, Montreal, QC, Canada
| | - N Mechawar
- McGill Group for Suicide Studies, McGill University, Douglas Mental Health University Institute, Montreal, QC, Canada.,Department of Psychiatry, McGill University, Douglas Mental Health University Institute, Montreal, QC, Canada
| | - G Turecki
- McGill Group for Suicide Studies, McGill University, Douglas Mental Health University Institute, Montreal, QC, Canada.,Department of Psychiatry, McGill University, Douglas Mental Health University Institute, Montreal, QC, Canada
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Gene-body 5-hydroxymethylation is associated with gene expression changes in the prefrontal cortex of depressed individuals. Transl Psychiatry 2017; 7:e1119. [PMID: 28485726 PMCID: PMC5534961 DOI: 10.1038/tp.2017.93] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 03/15/2017] [Accepted: 03/21/2017] [Indexed: 12/16/2022] Open
Abstract
5-Hydroxymethylcytosine (5hmC) is a recently characterized epigenetic mark that is particularly abundant in brain tissue and that regulates gene transcription. We have recently begun to understand the important role of 5hmC in brain development, plasticity and disease, but there are currently little data on 5hmC alterations in psychiatric illnesses. Here we report what we believe to be the first genome-wide analysis of 5hmC in the depressed brain. Using AbaSI sequencing, we investigated 5hmC in the prefrontal cortex of depressed (N=19) and psychiatrically healthy controls (N=19). Consistent with previous global 5hmC analyses in other phenotypes, and likely owing to the inter-individual variability in 5hmC content, the distribution of 5hmC across chromosomes and genomic features was not different between groups. We did, however, find 550 CpGs with suggestive evidence of differential hydroxymethylation. Of these, we validated CpGs in the gene body of myosin XVI (MYO16) and insulin-degrading enzyme using targeted oxidative bisulfite sequencing. Furthermore, the enrichment of 5hmC was also associated with changes in the expression of these two genes in depressed suicides. Together, our results present a novel mechanism linking increased 5hmC to depression and provide a framework for future research in this field.
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24
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Hodes GE, Walker DM, Labonté B, Nestler EJ, Russo SJ. Understanding the epigenetic basis of sex differences in depression. J Neurosci Res 2017; 95:692-702. [PMID: 27870456 PMCID: PMC5130105 DOI: 10.1002/jnr.23876] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 07/13/2016] [Accepted: 07/14/2016] [Indexed: 12/27/2022]
Abstract
Epigenetics refers to potentially heritable processes that can mediate both lasting and transient changes in gene expression in the absence of genome sequence alterations. The field of epigenetics has introduced a novel understanding of the mechanisms through which the environment can shape an individual and potentially its offspring. This Mini-Review examines the current literature exploring the role of epigenetics in the development of mood disorders such as depression. Depression is twofold more common in females, yet the majority of preclinical research has been conducted exclusively in male subjects. Here we discuss what is known about sex differences in epigenetic regulation and function and how this may contribute to the etiology and onset of mood disorders. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Georgia E. Hodes
- Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029
| | - Deena M. Walker
- Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029
| | - Benoit Labonté
- Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029
| | - Eric J. Nestler
- Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029
| | - Scott J. Russo
- Fishberg Department of Neuroscience and Freidman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029
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Understanding epigenetic architecture of suicide neurobiology: A critical perspective. Neurosci Biobehav Rev 2016; 72:10-27. [PMID: 27836463 DOI: 10.1016/j.neubiorev.2016.10.031] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 09/26/2016] [Accepted: 10/31/2016] [Indexed: 12/29/2022]
Abstract
Current understanding of environmental cross-talk with genetic makeup is found to be mediated through an epigenetic interface which is associated with prominent reversible and heritable changes at gene expression level. Recent emergence of epigenetic modulation in shaping the genetic information has become a key regulatory factor in answering the underlying complexities associated with several mental disorders. A comprehensive understanding of the pertinent changes in the epigenetic makeup of suicide phenotype exhibits a characteristic signature with the possibility of using it as a biomarker to help predict the risk factors associated with suicide. Within the scope of this current review, the most sought after epigenetic changes of DNA methylation and histone modification are thoroughly scrutinized to understand their close functional association with the broad spectrum of suicide phenotype.
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Abstract
Suicide ranks amongst the leading causes of death worldwide. Contemporary models of suicide risk posit that suicide results from the interaction of distal and proximal factors, including neurobiological, psychological/clinical, and social factors. While a wealth of neurobiological studies aimed at identifying biological processes associated with suicidal behaviour have been conducted over the last decades, the more recent development of arrays and high-throughput sequencing methods have led to an increased capacity and interest in the study of genomic factors. Postmortem studies are a unique tool to directly investigate genomic processes that may be dysregulated in the suicidal brain. In this review, we discuss postmortem literature investigating functional genomic studies of suicide, particularly focusing on epigenetic mechanisms.
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Affiliation(s)
- Daniel Almeida
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, 6875, LaSalle Boulevard, H4H 1R3, Verdun, Quebec, Canada
| | - Gustavo Turecki
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, 6875, LaSalle Boulevard, H4H 1R3, Verdun, Quebec, Canada.
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27
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Dissecting bipolar disorder complexity through epigenomic approach. Mol Psychiatry 2016; 21:1490-1498. [PMID: 27480490 PMCID: PMC5071130 DOI: 10.1038/mp.2016.123] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 06/09/2016] [Accepted: 06/13/2016] [Indexed: 01/16/2023]
Abstract
In recent years, numerous studies of gene regulation mechanisms have emerged in neuroscience. Epigenetic modifications, described as heritable but reversible changes, include DNA methylation, DNA hydroxymethylation, histone modifications and noncoding RNAs. The pathogenesis of psychiatric disorders, such as bipolar disorder, may be ascribed to a complex gene-environment interaction (G × E) model, linking the genome, environmental factors and epigenetic marks. Both the high complexity and the high heritability of bipolar disorder make it a compelling candidate for neurobiological analyses beyond DNA sequencing. Questions that are being raised in this review are the precise phenotype of the disorder in question, and also the trait versus state debate and how these concepts are being implemented in a variety of study designs.
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28
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Nagy C, Torres-Platas SG, Mechawar N, Turecki G. Repression of Astrocytic Connexins in Cortical and Subcortical Brain Regions and Prefrontal Enrichment of H3K9me3 in Depression and Suicide. Int J Neuropsychopharmacol 2016; 20:50-57. [PMID: 27516431 PMCID: PMC5737582 DOI: 10.1093/ijnp/pyw071] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Major depressive disorder has been associated with dysfunctional astrocytic networks. The underlying causes, extent, and consequences of such dysfunctions remain to be characterized. Astrocyte-astrocyte communication occurs principally through gap junction channels primarily formed by connexin 30 and 43 (CX30 and CX43). We previously reported decreased connexin expression in the prefrontal cortex of depressed suicides. In the present study, we investigated whether these changes are mediated by epigenetic regulation, and expanded gene expression quantifications to other cortical and subcortical regions to assess the regional distribution of connexion disruptions in depressed suicides. METHODS The expression of CX30 and CX43 was measured by real-time PCR in samples of neocortex (Brodmann areas 4 and 17), cerebellar cortex, mediodorsal thalamus, and caudate nucleus of 22 depressed suicides and 22 matched sudden-death controls. Chromatin immunoprecipitation was used to measure enrichment levels of the repressive chromatin mark H3K9me3 in the prefrontal cortex. RESULTS We found a consistent downregulation of connexin genes in all regions examined, except in the cerebellum where an increase in the expression of CX30 was measured and using chromatin immunoprecipitation we observed an enrichment of H3K9me3 for both Cx30 and Cx43 in the prefrontal cortex. CONCLUSIONS Our study shows widespread astrocytic CX gene repression in depressed suicides that is mediated, at least in part, through epigenetic mechanisms. Taken together, these findings support the notion of widespread cerebral astrocytic dysfunction in major depressive disorder.
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Affiliation(s)
- Corina Nagy
- McGill Group for Suicide Studies, Douglas Mental Health University Institute (Ms Nagy, Drs Torres-Platas, Machawar, and Turecki); Departments of Neurology and Neurosurgery (Ms Nagy, Drs Torres-Platas, Machawar, and Turecki), Human Genetics (Dr Turecki), and Psychiatry (Drs Mechawar and Turecki), McGill University, Verdun, Québec, Canada
| | - Susana G. Torres-Platas
- McGill Group for Suicide Studies, Douglas Mental Health University Institute (Ms Nagy, Drs Torres-Platas, Machawar, and Turecki); Departments of Neurology and Neurosurgery (Ms Nagy, Drs Torres-Platas, Machawar, and Turecki), Human Genetics (Dr Turecki), and Psychiatry (Drs Mechawar and Turecki), McGill University, Verdun, Québec, Canada
| | - Naguib Mechawar
- McGill Group for Suicide Studies, Douglas Mental Health University Institute (Ms Nagy, Drs Torres-Platas, Machawar, and Turecki); Departments of Neurology and Neurosurgery (Ms Nagy, Drs Torres-Platas, Machawar, and Turecki), Human Genetics (Dr Turecki), and Psychiatry (Drs Mechawar and Turecki), McGill University, Verdun, Québec, Canada
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29
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Guerra GP, Rubin MA, Mello CF. Modulation of learning and memory by natural polyamines. Pharmacol Res 2016; 112:99-118. [PMID: 27015893 DOI: 10.1016/j.phrs.2016.03.023] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Revised: 03/09/2016] [Accepted: 03/11/2016] [Indexed: 01/08/2023]
Abstract
Spermine and spermidine are natural polyamines that are produced mainly via decarboxylation of l-ornithine and the sequential transfer of aminopropyl groups from S-adenosylmethionine to putrescine by spermidine synthase and spermine synthase. Spermine and spermidine interact with intracellular and extracellular acidic residues of different nature, including nucleic acids, phospholipids, acidic proteins, carboxyl- and sulfate-containing polysaccharides. Therefore, multiple actions have been suggested for these polycations, including modulation of the activity of ionic channels, protein synthesis, protein kinases, and cell proliferation/death, within others. In this review we summarize these neurochemical/neurophysiological/morphological findings, particularly those that have been implicated in the improving and deleterious effects of spermine and spermidine on learning and memory of naïve animals in shock-motivated and nonshock-motivated tasks, from a historical perspective. The interaction with the opioid system, the facilitation and disruption of morphine-induced reward and the effect of polyamines and putative polyamine antagonists on animal models of cognitive diseases, such as Alzheimer's, Huntington, acute neuroinflammation and brain trauma are also reviewed and discussed. The increased production of polyamines in Alzheimer's disease and the biphasic nature of the effects of polyamines on memory and on the NMDA receptor are also considered. In light of the current literature on polyamines, which include the description of an inborn error of the metabolism characterized by mild-to moderate mental retardation and polyamine metabolism alterations in suicide completers, we can anticipate that polyamine targets may be important for the development of novel strategies and approaches for understanding the etiopathogenesis of important central disorders and their pharmacological treatment.
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Affiliation(s)
- Gustavo Petri Guerra
- Department of Food Technology, Federal Technological University of Paraná, Campus Medianeira, Medianeira, PR 85884-000, Brazil
| | - Maribel Antonello Rubin
- Department of Biochemistry, Center of Exact and Natural Sciences, Federal University of Santa Maria (UFSM), Santa Maria, RS 97105-900, Brazil.
| | - Carlos Fernando Mello
- Department of Physiology and Pharmacology, Center of Health Sciences, Federal University of Santa Maria (UFSM), Santa Maria, RS 97105-900, Brazil.
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30
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Dwivedi Y. Pathogenetic and therapeutic applications of microRNAs in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2016; 64:341-8. [PMID: 25689819 PMCID: PMC4537399 DOI: 10.1016/j.pnpbp.2015.02.003] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 02/04/2015] [Accepted: 02/06/2015] [Indexed: 01/08/2023]
Abstract
As a class of noncoding RNAs, microRNAs (miRNAs) regulate gene expression by inhibiting translation of messenger RNAs. These miRNAs have been shown to play a critical role in higher brain functioning and actively participate in synaptic plasticity. Pre-clinical evidence demonstrates that expression of miRNAs is differentially altered during stress. On the other hand, depressed individuals show marked changes in miRNA expression in brain. MiRNAs are also target of antidepressants and electroconvulsive therapy. Moreover, these miRNAs are present in circulating blood and can be easily detected. Profiling of miRNAs in blood plasma/serum provides evidence that determination of miRNAs in blood can be used as possible diagnostic and therapeutic tool. In this review article, these aspects are critically reviewed and the role of miRNAs in possible etiopathogenesis and therapeutic implications in the context of major depressive disorder is discussed.
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Affiliation(s)
- Yogesh Dwivedi
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, SC711 Sparks Center, 1720 2nd Avenue South, Birmingham, AL, USA.
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31
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Nestler EJ, Peña CJ, Kundakovic M, Mitchell A, Akbarian S. Epigenetic Basis of Mental Illness. Neuroscientist 2015; 22:447-63. [PMID: 26450593 DOI: 10.1177/1073858415608147] [Citation(s) in RCA: 215] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Psychiatric disorders are complex multifactorial illnesses involving chronic alterations in neural circuit structure and function as well as likely abnormalities in glial cells. While genetic factors are important in the etiology of most mental disorders, the relatively high rates of discordance among identical twins, particularly for depression and other stress-related syndromes, clearly indicate the importance of additional mechanisms. Environmental factors such as stress are known to play a role in the onset of these illnesses. Exposure to such environmental insults induces stable changes in gene expression, neural circuit function, and ultimately behavior, and these maladaptations appear distinct between developmental versus adult exposures. Increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Indeed, transcriptional dysregulation and the aberrant epigenetic regulation that underlies this dysregulation is a unifying theme in psychiatric disorders. Here, we provide a progress report of epigenetic studies of the three major psychiatric syndromes, depression, schizophrenia, and bipolar disorder. We review the literature derived from animal models of these disorders as well as from studies of postmortem brain tissue from human patients. While epigenetic studies of mental illness remain at early stages, understanding how environmental factors recruit the epigenetic machinery within specific brain regions to cause lasting changes in disease susceptibility and pathophysiology is revealing new insight into the etiology and treatment of these conditions.
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Affiliation(s)
- Eric J Nestler
- Departments of Neuroscience and Psychiatry, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Catherine J Peña
- Departments of Neuroscience and Psychiatry, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Marija Kundakovic
- Departments of Neuroscience and Psychiatry, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Amanda Mitchell
- Departments of Neuroscience and Psychiatry, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Schahram Akbarian
- Departments of Neuroscience and Psychiatry, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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32
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Bagot RC, Labonté B, Peña CJ, Nestler EJ. Epigenetic signaling in psychiatric disorders: stress and depression. DIALOGUES IN CLINICAL NEUROSCIENCE 2015. [PMID: 25364280 PMCID: PMC4214172 DOI: 10.31887/dcns.2014.16.3/rbagot] [Citation(s) in RCA: 124] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Psychiatric disorders are complex multifactorial disorders involving chronic alterations in neural circuit structure and function. While genetic factors play a role in the etiology of disorders such as depression, addiction, and schizophrenia, relatively high rates of discordance among identical twins clearly point to the importance of additional factors. Environmental factors, such as stress, play a major role in the psychiatric disorders by inducing stable changes in gene expression, neural circuit function, and ultimately behavior. Insults at the developmental stage and in adulthood appear to induce distinct maladaptations. Increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Indeed, transcriptional dysregulation and associated aberrant epigenetic regulation is a unifying theme in psychiatric disorders. Aspects of depression can be modeled in animals by inducing disease-like states through environmental manipulations, and these studies can provide a more general understanding of epigenetic mechanisms in psychiatric disorders. Understanding how environmental factors recruit the epigenetic machinery in animal models is providing new insights into disease mechanisms in humans.
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Affiliation(s)
- Rosemary C Bagot
- Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Benoit Labonté
- Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Catherine J Peña
- Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Eric J Nestler
- Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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33
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Sokolowski M, Wasserman J, Wasserman D. An overview of the neurobiology of suicidal behaviors as one meta-system. Mol Psychiatry 2015; 20:56-71. [PMID: 25178164 DOI: 10.1038/mp.2014.101] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 06/19/2014] [Accepted: 07/22/2014] [Indexed: 12/12/2022]
Abstract
Suicidal behaviors (SB) may be regarded as the outmost consequence of mental illnesses, or as a distinct entity per se. Regardless, the consequences of SB are very large to both society and affected individuals. The path leading to SB is clearly a complex one involving interactions between the subject's biology and environmental influences throughout life. With the aim to generate a representative and diversified overview of the different neurobiological components hypothesized or shown implicated across the entire SB field up to date by any approach, we selected and compiled a list of 212 gene symbols from the literature. An increasing number of novel gene (products) have been introduced as candidates, with half being implicated in SB in only the last 4 years. These candidates represent different neuro systems and functions and might therefore be regarded as competing or redundant explanations. We then adopted a unifying approach by treating them all as parts of the same meta-system, using bioinformatic tools. We present a network of all components connected by physical protein-protein interactions (the SB interactome). We proceeded by exploring the differences between the highly connected core (~30% of the candidate genes) and its peripheral parts, observing more functional homogeneity at the core, with multiple signal transduction pathways and actin-interacting proteins connecting a subset of receptors in nerve cell compartments as well as development/morphology phenotypes and the stress-sensitive synaptic plasticity processes of long term potentiation/depression. We suggest that SB neurobiology might also be viewed as one meta-system and perhaps be explained as intrinsic unbalances acting within the core or as imbalances arising between core and specific peripheral components.
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Affiliation(s)
- M Sokolowski
- National Centre for Suicide Research and Prevention of Mental Ill-Health (NASP), Karolinska Institute (KI), Stockholm, Sweden
| | - J Wasserman
- National Centre for Suicide Research and Prevention of Mental Ill-Health (NASP), Karolinska Institute (KI), Stockholm, Sweden
| | - D Wasserman
- 1] National Centre for Suicide Research and Prevention of Mental Ill-Health (NASP), Karolinska Institute (KI), Stockholm, Sweden [2] WHO Collaborating Centre for Research, Methods Development and Training in Suicide Prevention, Stockholm, Sweden
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34
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Abstract
Recent studies have shown an association between gene alterations by epigenetic mechanisms and suicidal behavior. These epigenetic mechanisms are mitotically, and in some cases meiotically, heritable changes in the genome through non-DNA sequence coding processes that alter gene expression as a result of variable changes in environmental stimuli. Genome-wide association studies have been inconsistent in elucidating the association between genes and suicidal behavior, thereby making the heritability of suicidal behavior is unclear. However, recent epigenetic studies have provided evidence that epigenetic mechanisms could deliver the missing link between the heritability of suicidal behavior and the interaction between environment and the genome. The present review provides an in-depth discussion of epigenetic mechanisms that may regulate gene expression in suicidal behavior. The findings of current epigenetic studies on suicidal behavior will also be discussed considering future epigenome-wide association studies on elucidating the contributions of environment and genome on suicidal behavior.
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Affiliation(s)
- Ali Bani-Fatemi
- a Group for Suicide Studies, CAMH, Department of Psychiatry , University of Toronto , Toronto , Canada
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35
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Gross JA, Turecki G. Suicide and the polyamine system. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2014; 12:980-8. [PMID: 24040803 DOI: 10.2174/18715273113129990095] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Revised: 12/02/2012] [Accepted: 12/02/2012] [Indexed: 12/27/2022]
Abstract
Suicide is a significant worldwide public health problem. Understanding the neurobiology is important as it can help us to better elucidate underlying etiological factors and provide opportunities for intervention. In recent years, many lines of research have suggested that the polyamine system may be dysregulated in suicidal behaviors. Initial research in animals provided evidence of a dysfunctional polyamine stress response system, while later work using post-mortem human brain tissue has suggested that molecular mechanisms may be at play in the suicide brain. In this review, we will describe the research that suggests the presence of alterations in the polyamine system in mental disorders and behavioral phenotypes, with particular attention to work on suicide. In addition, we will also describe potential avenues for future work.
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Affiliation(s)
- Jeffrey A Gross
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, 6875 boul. Lasalle, Verdun, Quebec, H4H 1R3, Canada.
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36
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Abstract
Suicide ranks among the leading causes of death around the world and takes a heavy emotional and public health toll on most societies. Both distal and proximal factors contribute to suicidal behaviour. Distal factors - such as familial and genetic predisposition, as well as early-life adversity - increase the lifetime risk of suicide. They alter responses to stress and other processes through epigenetic modification of genes and associated changes in gene expression, and through the regulation of emotional and behavioural traits. Proximal factors are associated with the precipitation of a suicidal event and include alterations in key neurotransmitter systems, inflammatory changes and glial dysfunction in the brain. This Review explores the key molecular changes that are associated with suicidality and discusses some promising avenues for future research.
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37
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Turecki G. Epigenetics and suicidal behavior research pathways. Am J Prev Med 2014; 47:S144-51. [PMID: 25145732 PMCID: PMC5319855 DOI: 10.1016/j.amepre.2014.06.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Revised: 05/27/2014] [Accepted: 06/10/2014] [Indexed: 10/24/2022]
Abstract
Suicide and suicidal behaviors are complex, heterogeneous phenomena that are thought to result from the interactions among distal factors increasing predisposition and proximal factors acting as precipitants. Epigenetic factors are likely to act both distally and proximally. Aspirational Goal 1 aims to find clear targets for suicide and suicidal behavior intervention through greater understanding of the interplay among the biological, psychological, and social risk and protective factors associated with suicide. This paper discusses Aspirational Goal 1, focusing on the research pathway related to epigenetics, suicide, and suicidal behaviors. Current knowledge on epigenetic factors associated with suicide and suicidal behaviors is reviewed and avenues for future research are discussed. Epigenetic factors are a promising area of further investigation in the understanding of suicide and suicidal behaviors and may hold clues to identifying targets or avenues for intervention.
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Affiliation(s)
- Gustavo Turecki
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
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38
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Epigenetic signaling in psychiatric disorders. J Mol Biol 2014; 426:3389-412. [PMID: 24709417 DOI: 10.1016/j.jmb.2014.03.016] [Citation(s) in RCA: 112] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 03/28/2014] [Accepted: 03/31/2014] [Indexed: 01/10/2023]
Abstract
Psychiatric disorders are complex multifactorial illnesses involving chronic alterations in neural circuit structure and function. While genetic factors are important in the etiology of disorders such as depression and addiction, relatively high rates of discordance among identical twins clearly indicate the importance of additional mechanisms. Environmental factors such as stress or prior drug exposure are known to play a role in the onset of these illnesses. Such exposure to environmental insults induces stable changes in gene expression, neural circuit function, and ultimately behavior, and these maladaptations appear distinct between developmental and adult exposures. Increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Indeed, transcriptional dysregulation and associated aberrant epigenetic regulation is a unifying theme in psychiatric disorders. Aspects of depression and addiction can be modeled in animals by inducing disease-like states through environmental manipulations (e.g., chronic stress, drug administration). Understanding how environmental factors recruit the epigenetic machinery in animal models reveals new insight into disease mechanisms in humans.
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39
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Abstract
Suicide and bipolar disorder (BD) are challenging, complex, and intertwined areas of study in contemporary psychiatry. Indeed, BD is associated with the highest lifetime risk for suicide attempt and completion of all the psychiatric conditions. Given that several clinical risk factors for both suicide and BD have been well noted in the literature, exploring the neurobiological aspects of suicide in BD may provide insights into both preventive measures and future novel treatments. This review synthesizes findings regarding the neurobiological aspects of suicide and, when applicable, their link to BD. Neurochemical findings, genes/epigenetics, and potential molecular targets for current or future treatments are discussed. The role of endophenotypes and related proximal and distal risk factors underlying suicidal behavior are also explored. Lastly, we discuss the manner in which preclinical work on aggression and impulsivity may provide additional insights for the future development of novel treatments.
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El-Sayed AM, Haloossim MR, Galea S, Koenen KC. Epigenetic modifications associated with suicide and common mood and anxiety disorders: a systematic review of the literature. BIOLOGY OF MOOD & ANXIETY DISORDERS 2012; 2:10. [PMID: 22738307 PMCID: PMC3495635 DOI: 10.1186/2045-5380-2-10] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2012] [Accepted: 05/18/2012] [Indexed: 11/29/2022]
Abstract
Epigenetic modifications are those reversible, mitotically heritable alterations in genomic expression that occur independent of changes in gene sequence. Epigenetic studies have the potential to improve our understanding of the etiology of mood and anxiety disorders and suicide by bridging the gap in knowledge between the exogenous environmental exposures and pathophysiology that produce common mood and anxiety disorders and suicide. We systematically reviewed the English-language peer-reviewed literature about epigenetic regulation in these disorders between 2001–2011, summarizing and synthesizing this literature with respect to directions for future work. Twenty-one articles met our inclusion criteria. Twelve studies were concerned with epigenetic changes among suicide completers; other studies considered epigenetic regulation in depression, post-traumatic stress disorder, and panic disorder. Several studies focused on epigenetic regulation of amine, glucocorticoid, and serotonin metabolism in the production of common mood and anxiety disorders and suicide. The literature is nascent and has yet to reach consensus about the roles of particular epigenetic modifications in the etiology of these outcomes. Future studies require larger sample sizes and measurements of environmental exposures antecedent to epigenetic modification. Further work is also needed to clarify the link between epigenetic modifications in the brain and peripheral tissues and to establish ‘gold standard’ epigenetic assays.
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Affiliation(s)
- Abdulrahman M El-Sayed
- Department of Epidemiology, Mailman School of Public Health, Columbia University, 722 W, 168th Street, R521, New York, NY 10032, USA.
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Cervelli M, Amendola R, Polticelli F, Mariottini P. Spermine oxidase: ten years after. Amino Acids 2012; 42:441-50. [PMID: 21809080 DOI: 10.1007/s00726-011-1014-z] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Accepted: 05/25/2011] [Indexed: 12/13/2022]
Abstract
Spermine oxidase (SMO) was discovered much more recently than other enzymes involved in polyamine metabolism; this review summarizes 10 years of researches on this enzyme. Spermine oxidase (SMO) is a FAD-dependent enzyme that specifically oxidizes spermine (Spm) and plays a dominant role in the highly regulated mammalian polyamines catabolism. SMO participates in drug response, apoptosis, response to stressful stimuli and etiology of several pathological conditions, including cancer. SMO is a highly inducible enzyme, its deregulation can alter polyamine homeostasis, and dysregulation of polyamine catabolism is often associated with several disease states. The oxidative products of SMO activity are spermidine, and the reactive oxygen species H(2)O(2) and the aldehyde 3-aminopropanal each with the potential to produce cellular damages and pathologies. The SMO substrate Spm is a tetramine that plays mandatory roles in several cell functions, such as DNA synthesis, cellular proliferation, modulation of ion channels function, cellular signaling, nitric oxide synthesis and inhibition of immune responses. The goal of this review is to cover the main biochemical, cellular and physiological processes in which SMO is involved.
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Turecki G, Ernst C, Jollant F, Labonté B, Mechawar N. The neurodevelopmental origins of suicidal behavior. Trends Neurosci 2011; 35:14-23. [PMID: 22177979 DOI: 10.1016/j.tins.2011.11.008] [Citation(s) in RCA: 183] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Revised: 10/28/2011] [Accepted: 11/21/2011] [Indexed: 12/30/2022]
Abstract
Suicide and related behaviors are complex phenomena associated with different risk factors. Although most individuals who display suicidal behavior do not have a history of early-life adversity, a significant minority does. Recent animal and human data have suggested that early-life adversity leads to epigenetic regulation of genes involved in stress-response systems. Here, we review this evidence and suggest that early-life adversity increases risk of suicide in susceptible individuals by influencing the development of stable emotional, behavioral and cognitive phenotypes that are likely to result from the epigenetic regulation of the hypothalamic-pituitary-adrenal axis and other systems involved in responses to stress.
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Affiliation(s)
- Gustavo Turecki
- McGill Group for Suicide Studies, Department of Psychiatry, McGill University, Montreal, Canada.
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