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Kisil O, Sergeev A, Bacheva A, Zvereva M. Methods for Detection and Mapping of Methylated and Hydroxymethylated Cytosine in DNA. Biomolecules 2024; 14:1346. [PMID: 39595523 PMCID: PMC11591845 DOI: 10.3390/biom14111346] [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: 08/29/2024] [Revised: 10/11/2024] [Accepted: 10/15/2024] [Indexed: 11/28/2024] Open
Abstract
The chemical modifications of DNA are of pivotal importance in the epigenetic regulation of cellular processes. Although the function of 5-methylcytosine (5mC) has been extensively investigated, the significance of 5-hydroxymethylcytosine (5hmC) has only recently been acknowledged. Conventional methods for the detection of DNA methylation frequently lack the capacity to distinguish between 5mC and 5hmC, resulting in the combined reporting of both. The growing importance of 5hmC has prompted the development of a multitude of methods for the qualitative and quantitative analysis of 5hmC in recent years, thereby facilitating researchers' understanding of the mechanisms underlying the onset and progression of numerous diseases. This review covers both established and novel methods for the detection of cytosine modifications, including 5mC, 5hmC, 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), with a particular focus on those that allow for accurate mapping and detection, particularly with third-generation sequencing. The review aims to help researchers choose the most appropriate methods based on their specific research goals and budget.
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Affiliation(s)
- Olga Kisil
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russia; (O.K.); (A.B.); (M.Z.)
- Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia
| | - Alexander Sergeev
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russia; (O.K.); (A.B.); (M.Z.)
- Orekhovich Institute of Biomedical Chemistry, Pogodinskaya Street, 10/8, Moscow 119121, Russia
| | - Anna Bacheva
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russia; (O.K.); (A.B.); (M.Z.)
| | - Maria Zvereva
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russia; (O.K.); (A.B.); (M.Z.)
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Montgomery T, Uh K, Lee K. TET enzyme driven epigenetic reprogramming in early embryos and its implication on long-term health. Front Cell Dev Biol 2024; 12:1358649. [PMID: 39149518 PMCID: PMC11324557 DOI: 10.3389/fcell.2024.1358649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 07/23/2024] [Indexed: 08/17/2024] Open
Abstract
Mammalian embryo development is initiated by the union of paternal and maternal gametes. Upon fertilization, their epigenome landscape is transformed through a series of finely orchestrated mechanisms that are crucial for survival and successful embryogenesis. Specifically, maternal or oocyte-specific reprogramming factors modulate germ cell specific epigenetic marks into their embryonic states. Rapid and dynamic changes in epigenetic marks such as DNA methylation and histone modifications are observed during early embryo development. These changes govern the structure of embryonic genome prior to zygotic genome activation. Differential changes in epigenetic marks are observed between paternal and maternal genomes because the structure of the parental genomes allows interaction with specific oocyte reprogramming factors. For instance, the paternal genome is targeted by the TET family of enzymes which oxidize the 5-methylcytosine (5mC) epigenetic mark into 5-hydroxymethylcytosine (5hmC) to lower the level of DNA methylation. The maternal genome is mainly protected from TET3-mediated oxidation by the maternal factor, STELLA. The TET3-mediated DNA demethylation occurs at the global level and is clearly observed in many mammalian species. Other epigenetic modulating enzymes, such as DNA methyltransferases, provide fine tuning of the DNA methylation level by initiating de novo methylation. The mechanisms which initiate the epigenetic reprogramming of gametes are critical for proper activation of embryonic genome and subsequent establishment of pluripotency and normal development. Clinical cases or diseases linked to mutations in reprogramming modulators exist, emphasizing the need to understand mechanistic actions of these modulators. In addition, embryos generated via in vitro embryo production system often present epigenetic abnormalities. Understanding mechanistic actions of the epigenetic modulators will potentially improve the well-being of individuals suffering from these epigenetic disorders and correct epigenetic abnormalities in embryos produced in vitro. This review will summarize the current understanding of epigenetic reprogramming by TET enzymes during early embryogenesis and highlight its clinical relevance and potential implication for assisted reproductive technologies.
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Affiliation(s)
- Ty Montgomery
- Division of Animal Sciences, University of Missouri, Columbia, MO, United States
| | - Kyungjun Uh
- Futuristic Animal Resource and Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju-si, Republic of Korea
| | - Kiho Lee
- Division of Animal Sciences, University of Missouri, Columbia, MO, United States
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Huang M, Wang J, Liu W, Zhou H. Advances in the role of the GADD45 family in neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. Front Neurosci 2024; 18:1349409. [PMID: 38332860 PMCID: PMC10850240 DOI: 10.3389/fnins.2024.1349409] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 01/10/2024] [Indexed: 02/10/2024] Open
Abstract
The growth arrest and DNA damage inducible protein 45 (GADD45) family comprises stress-induced nuclear proteins that interact with DNA demethylases to facilitate DNA demethylation, thereby regulating diverse cellular processes including oxidative stress, DNA damage repair, apoptosis, proliferation, differentiation, inflammation, and neuroplasticity by modulating the expression patterns of specific genes. Widely expressed in the central nervous system, the GADD45 family plays a pivotal role in various neurological disorders, rendering it a potential therapeutic target for central nervous system diseases. This review presented a comprehensive overview of the expression patterns and potential mechanisms of action associated with each member of GADD45 family (GADD45α, GADD45β, and GADD45γ) in neurodevelopmental, neurodegenerative, and neuropsychiatric disorders, while also explored strategies to harness these mechanisms for intervention and treatment. Future research should prioritize the development of effective modulators targeting the GADD45 family for clinical trials aimed at treating central nervous system diseases.
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Affiliation(s)
| | | | | | - Hongyan Zhou
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China
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Leon Kropf V, Albany CJ, Zoccarato A, Green HLH, Yang Y, Brewer AC. TET3 is a positive regulator of mitochondrial respiration in Neuro2A cells. PLoS One 2024; 19:e0294187. [PMID: 38227585 PMCID: PMC10790995 DOI: 10.1371/journal.pone.0294187] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 10/26/2023] [Indexed: 01/18/2024] Open
Abstract
Ten-Eleven-Translocase (TET) enzymes contribute to the regulation of the methylome via successive oxidation of 5-methyl cytosine (5mC) to derivatives which can be actively removed by base-excision-repair (BER) mechanisms in the absence of cell division. This is particularly important in post-mitotic neurons where changes in DNA methylation are known to associate with changes in neural function. TET3, specifically, is a critical regulator of both neuronal differentiation in development and mediates dynamic changes in the methylome of adult neurons associated with cognitive function. While DNA methylation is understood to regulate transcription, little is known of the specific targets of TET3-dependent catalytic activity in neurons. We report the results of an unbiased transcriptome analysis of the neuroblastoma-derived cell line; Neuro2A, in which Tet3 was silenced. Oxidative phosphorylation (OxPhos) was identified as the most significantly down-regulated functional canonical pathway, and these findings were confirmed by measurements of oxygen consumption rate in the Seahorse bioenergetics analyser. The mRNA levels of both nuclear- and mitochondrial-encoded OxPhos genes were reduced by Tet3-silencing, but we found no evidence for differential (hydroxy)methylation deposition at these gene loci. However, the mRNA expression of genes known to be involved in mitochondrial quality control were also shown to be significantly downregulated in the absence of TET3. One of these genes; EndoG, was identified as a direct target of TET3-catalytic activity at non-CpG methylated sites within its gene body. Accordingly, we propose that aberrant mitochondrial homeostasis may contribute to the decrease in OxPhos, observed upon Tet3-downregulation in Neuro2A cells.
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Affiliation(s)
- Valeria Leon Kropf
- School of Cardiovascular and Metabolic Medicine & Sciences, King’s College London British Heart Foundation Centre of Excellence, London, United Kingdom
| | - Caraugh J. Albany
- School of Cardiovascular and Metabolic Medicine & Sciences, King’s College London British Heart Foundation Centre of Excellence, London, United Kingdom
| | - Anna Zoccarato
- School of Cardiovascular and Metabolic Medicine & Sciences, King’s College London British Heart Foundation Centre of Excellence, London, United Kingdom
| | - Hannah L. H. Green
- School of Cardiovascular and Metabolic Medicine & Sciences, King’s College London British Heart Foundation Centre of Excellence, London, United Kingdom
| | - Youwen Yang
- School of Cardiovascular and Metabolic Medicine & Sciences, King’s College London British Heart Foundation Centre of Excellence, London, United Kingdom
| | - Alison C. Brewer
- School of Cardiovascular and Metabolic Medicine & Sciences, King’s College London British Heart Foundation Centre of Excellence, London, United Kingdom
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Xie J, Wang Y, Ye C, Li XJ, Lin L. Distinctive Patterns of 5-Methylcytosine and 5-Hydroxymethylcytosine in Schizophrenia. Int J Mol Sci 2024; 25:636. [PMID: 38203806 PMCID: PMC10779130 DOI: 10.3390/ijms25010636] [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: 11/30/2023] [Revised: 12/25/2023] [Accepted: 12/30/2023] [Indexed: 01/12/2024] Open
Abstract
Schizophrenia is a highly heritable neuropsychiatric disorder characterized by cognitive and social dysfunction. Genetic, epigenetic, and environmental factors are together implicated in the pathogenesis and development of schizophrenia. DNA methylation, 5-methycytosine (5mC) and 5-hydroxylcytosine (5hmC) have been recognized as key epigenetic elements in neurodevelopment, ageing, and neurodegenerative diseases. Recently, distinctive 5mC and 5hmC pattern and expression changes of related genes have been discovered in schizophrenia. Antipsychotic drugs that affect 5mC status can alleviate symptoms in patients with schizophrenia, suggesting a critical role for DNA methylation in the pathogenesis of schizophrenia. Further exploring the signatures of 5mC and 5hmC in schizophrenia and developing precision-targeted epigenetic drugs based on this will provide new insights into the diagnosis and treatment of schizophrenia.
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Affiliation(s)
| | | | | | | | - Li Lin
- Guangdong Key Laboratory of Non-Human Primate Research, Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; (J.X.); (Y.W.); (C.Y.); (X.-J.L.)
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Ghanbari M, Khosroshahi NS, Alamdar M, Abdi A, Aghazadeh A, Feizi MAH, Haghi M. An Updated Review on the Significance of DNA and Protein Methyltransferases and De-methylases in Human Diseases: From Molecular Mechanism to Novel Therapeutic Approaches. Curr Med Chem 2024; 31:3550-3587. [PMID: 37287285 DOI: 10.2174/0929867330666230607124803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 05/05/2023] [Accepted: 05/09/2023] [Indexed: 06/09/2023]
Abstract
Epigenetic mechanisms are crucial in regulating gene expression. These mechanisms include DNA methylation and histone modifications, like methylation, acetylation, and phosphorylation. DNA methylation is associated with gene expression suppression; however, histone methylation can stimulate or repress gene expression depending on the methylation pattern of lysine or arginine residues on histones. These modifications are key factors in mediating the environmental effect on gene expression regulation. Therefore, their aberrant activity is associated with the development of various diseases. The current study aimed to review the significance of DNA and histone methyltransferases and demethylases in developing various conditions, like cardiovascular diseases, myopathies, diabetes, obesity, osteoporosis, cancer, aging, and central nervous system conditions. A better understanding of the epigenetic roles in developing diseases can pave the way for developing novel therapeutic approaches for affected patients.
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Affiliation(s)
- Mohammad Ghanbari
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Negin Sadi Khosroshahi
- Department of Biology, Faculty of Basic Sciences, Azarbaijan Shahid Madani University, Tabriz, Iran
| | - Maryam Alamdar
- Department of Genetics Sciences, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Adel Abdi
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Aida Aghazadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | - Mehdi Haghi
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
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Flynn LT, Gao WJ. DNA methylation and the opposing NMDAR dysfunction in schizophrenia and major depression disorders: a converging model for the therapeutic effects of psychedelic compounds in the treatment of psychiatric illness. Mol Psychiatry 2023; 28:4553-4567. [PMID: 37679470 PMCID: PMC11034997 DOI: 10.1038/s41380-023-02235-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 08/17/2023] [Accepted: 08/22/2023] [Indexed: 09/09/2023]
Abstract
Psychedelic compounds are being increasingly explored as a potential therapeutic option for treating several psychiatric conditions, despite relatively little being known about their mechanism of action. One such possible mechanism, DNA methylation, is a process of epigenetic regulation that changes gene expression via chemical modification of nitrogenous bases. DNA methylation has been implicated in the pathophysiology of several psychiatric conditions, including schizophrenia (SZ) and major depressive disorder (MDD). In this review, we propose alterations to DNA methylation as a converging model for the therapeutic effects of psychedelic compounds, highlighting the N-methyl D-aspartate receptor (NMDAR), a crucial mediator of synaptic plasticity with known dysfunction in both diseases, as an example and anchoring point. We review the established evidence relating aberrant DNA methylation to NMDAR dysfunction in SZ and MDD and provide a model asserting that psychedelic substances may act through an epigenetic mechanism to provide therapeutic effects in the context of these disorders.
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Affiliation(s)
- L Taylor Flynn
- Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA
- MD/PhD program, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Wen-Jun Gao
- Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA.
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Kouter K, Šalamon Arčan I, Videtič Paska A. Epigenetics in psychiatry: Beyond DNA methylation. World J Psychiatry 2023; 13:319-330. [PMID: 37383287 PMCID: PMC10294132 DOI: 10.5498/wjp.v13.i6.319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/31/2023] [Accepted: 04/25/2023] [Indexed: 06/19/2023] Open
Abstract
The global burden of psychopathologies appears to be underestimated, since the global psychiatric disorder burden is exceeding other medical burdens. To be able to address this problem more effectively, we need to better understand the etiology of psychiatric disorders. One of the hallmarks of psychiatric disorders appears to be epigenetic dysregulation. While some epigenetic modifications (such as DNA methylation) are well known and studied, the roles of others have been investigated much less. DNA hydroxymethylation is a rarely studied epigenetic modification, which as well as being an intermediate stage in the DNA demethylation cycle is also an independent steady cell state involved in neurodevelopment and plasticity. In contrast to DNA methylation, DNA hydroxymethylation appears to be related to an increase in gene expression and subsequent protein expression. Although no particular gene or genetic locus can be at this point linked to changes in DNA hydroxymethylation in psychiatric disorders, the epigenetic marks present good potential for biomarker identification because the epigenetic landscape is a result of the interplay between genes and environment, which both influence the development of psychiatric disorders, and because hydoxymethylation changes are particularly enriched in the brain and in synapse-related genes.
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Affiliation(s)
- Katarina Kouter
- Faculty of Medicine, Institute of Microbiology and Immunology, University of Ljubljana, Ljubljana 1000, Slovenia
| | - Iris Šalamon Arčan
- Faculty of Medicine, Institute of Biochemistry and Molecular Genetics, University of Ljubljana, Ljubljana 1000, Slovenia
| | - Alja Videtič Paska
- Faculty of Medicine, Institute of Biochemistry and Molecular Genetics, University of Ljubljana, Ljubljana 1000, Slovenia
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Kumar A, Kos MZ, Roybal D, Carless MA. A pilot investigation of differential hydroxymethylation levels in patient-derived neural stem cells implicates altered cortical development in bipolar disorder. Front Psychiatry 2023; 14:1077415. [PMID: 37139321 PMCID: PMC10150707 DOI: 10.3389/fpsyt.2023.1077415] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 03/24/2023] [Indexed: 05/05/2023] Open
Abstract
Introduction Bipolar disorder (BD) is a chronic mental illness characterized by recurrent episodes of mania and depression and associated with social and cognitive disturbances. Environmental factors, such as maternal smoking and childhood trauma, are believed to modulate risk genotypes and contribute to the pathogenesis of BD, suggesting a key role in epigenetic regulation during neurodevelopment. 5-hydroxymethylcytosine (5hmC) is an epigenetic variant of particular interest, as it is highly expressed in the brain and is implicated in neurodevelopment, and psychiatric and neurological disorders. Methods Induced pluripotent stem cells (iPSCs) were generated from the white blood cells of two adolescent patients with bipolar disorder and their same-sex age-matched unaffected siblings (n = 4). Further, iPSCs were differentiated into neuronal stem cells (NSCs) and characterized for purity using immuno-fluorescence. We used reduced representation hydroxymethylation profiling (RRHP) to perform genome-wide 5hmC profiling of iPSCs and NSCs, to model 5hmC changes during neuronal differentiation and assess their impact on BD risk. Functional annotation and enrichment testing of genes harboring differentiated 5hmC loci were performed with the online tool DAVID. Results Approximately 2 million sites were mapped and quantified, with the majority (68.8%) located in genic regions, with elevated 5hmC levels per site observed for 3' UTRs, exons, and 2-kb shorelines of CpG islands. Paired t-tests of normalized 5hmC counts between iPSC and NSC cell lines revealed global hypo-hydroxymethylation in NSCs and enrichment of differentially hydroxymethylated sites within genes associated with plasma membrane (FDR = 9.1 × 10-12) and axon guidance (FDR = 2.1 × 10-6), among other neuronal processes. The most significant difference was observed for a transcription factor binding site for the KCNK9 gene (p = 8.8 × 10-6), encoding a potassium channel protein involved in neuronal activity and migration. Protein-protein-interaction (PPI) networking showed significant connectivity (p = 3.2 × 10-10) between proteins encoded by genes harboring highly differentiated 5hmC sites, with genes involved in axon guidance and ion transmembrane transport forming distinct sub-clusters. Comparison of NSCs of BD cases and unaffected siblings revealed additional patterns of differentiation in hydroxymethylation levels, including sites in genes with functions related to synapse formation and regulation, such as CUX2 (p = 2.4 × 10-5) and DOK-7 (p = 3.6 × 10-3), as well as an enrichment of genes involved in the extracellular matrix (FDR = 1.0 × 10-8). Discussion Together, these preliminary results lend evidence toward a potential role for 5hmC in both early neuronal differentiation and BD risk, with validation and more comprehensive characterization to be achieved through follow-up study.
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Affiliation(s)
- Ashish Kumar
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, United States
- Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Mark Z. Kos
- South Texas Diabetes and Obesity Institute, Department of Human Genetics, The University of Texas Rio Grande Valley School of Medicine, San Antonio, TX, United States
| | - Donna Roybal
- Traditions Behavioral Health, Larkspur, CA, United States
- Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio, San Antonio, TX, United States
| | - Melanie A. Carless
- Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, United States
- Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio, San Antonio, TX, United States
- Brain Health Consortium, The University of Texas at San Antonio, San Antonio, TX, United States
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10
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Cheng Y, Song H, Ming GL, Weng YL. Epigenetic and epitranscriptomic regulation of axon regeneration. Mol Psychiatry 2023; 28:1440-1450. [PMID: 36922674 PMCID: PMC10650481 DOI: 10.1038/s41380-023-02028-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 02/27/2023] [Accepted: 03/01/2023] [Indexed: 03/18/2023]
Abstract
Effective axonal regeneration in the adult mammalian nervous system requires coordination of elevated intrinsic growth capacity and decreased responses to the inhibitory environment. Intrinsic regenerative capacity largely depends on the gene regulatory network and protein translation machinery. A failure to activate these pathways upon injury is underlying a lack of robust axon regeneration in the mature mammalian central nervous system. Epigenetics and epitranscriptomics are key regulatory mechanisms that shape gene expression and protein translation. Here, we provide an overview of different types of modifications on DNA, histones, and RNA, underpinning the regenerative competence of axons in the mature mammalian peripheral and central nervous systems. We highlight other non-neuronal cells and their epigenetic changes in determining the microenvironment for tissue repair and axon regeneration. We also address advancements of single-cell technology in charting transcriptomic and epigenetic landscapes that may further facilitate the mechanistic understanding of differential regenerative capacity in neuronal subtypes. Finally, as epigenetic and epitranscriptomic processes are commonly affected by brain injuries and psychiatric disorders, understanding their alterations upon brain injury would provide unprecedented mechanistic insights into etiology of injury-associated-psychiatric disorders and facilitate the development of therapeutic interventions to restore brain function.
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Affiliation(s)
- Yating Cheng
- Department of Neurosurgery, Houston Methodist Neurological Institute, Houston, TX, 77030, USA
- Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, 77030, USA
| | - Hongjun Song
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- The Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Guo-Li Ming
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
| | - Yi-Lan Weng
- Department of Neurosurgery, Houston Methodist Neurological Institute, Houston, TX, 77030, USA.
- Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, 77030, USA.
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11
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Xia M, Yan R, Kim MH, Xu X. Tet Enzyme-Mediated Response in Environmental Stress and Stress-Related Psychiatric Diseases. Mol Neurobiol 2023; 60:1594-1608. [PMID: 36534335 DOI: 10.1007/s12035-022-03168-9] [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: 08/08/2022] [Accepted: 12/10/2022] [Indexed: 12/23/2022]
Abstract
Mental disorders caused by stress have become a worldwide public health problem. These mental disorders are often the results of a combination of genes and environment, in which epigenetic modifications play a crucial role. At present, the genetic and epigenetic mechanisms of mental disorders such as posttraumatic stress disorder or depression caused by environmental stress are not entirely clear. Although many epigenetic modifications affect gene regulation, the most well-known modification in eukaryotic cells is the DNA methylation of CpG islands. Stress causes changes in DNA methylation in the brain to participate in the neuronal function or mood-modulating behaviors, and these epigenetic modifications can be passed on to offspring. Ten-eleven translocation (Tet) enzymes are the 5-methylcytosine (5mC) hydroxylases of DNA, which recognize 5mC on the DNA sequence and oxidize it to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Tet regulates gene expression at the transcriptional level through the demethylation of DNA. This review will elaborate on the molecular mechanism and the functions of Tet enzymes in environmental stress-related disorders and discuss future research directions.
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Affiliation(s)
- Meiling Xia
- Departments of Neurology, the Second Affiliated Hospital of Soochow University, Suzhou City, 215006, China.,Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul City, 03080, Korea
| | - Rui Yan
- Institute of Neuroscience, Soochow University, Suzhou City, China
| | - Myoung-Hwan Kim
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul City, 03080, Korea.
| | - Xingshun Xu
- Departments of Neurology, the Second Affiliated Hospital of Soochow University, Suzhou City, 215006, China. .,Institute of Neuroscience, Soochow University, Suzhou City, China. .,Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou City, China.
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12
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Pratt KJB, Shea JM, Remesal-Gomez L, Bieri G, Smith LK, Couthouis J, Chen CP, Roy IJ, Gontier G, Villeda SA. Loss of neuronal Tet2 enhances hippocampal-dependent cognitive function. Cell Rep 2022; 41:111612. [PMID: 36351399 PMCID: PMC10032941 DOI: 10.1016/j.celrep.2022.111612] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 08/04/2022] [Accepted: 10/13/2022] [Indexed: 11/09/2022] Open
Abstract
DNA methylation has emerged as a critical modulator of neuronal plasticity and cognitive function. Notwithstanding, the role of enzymes that demethylate DNA remain to be fully explored. Here, we report that loss of ten-eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), in adult neurons enhances cognitive function. In the adult mouse hippocampus, we detected an enrichment of Tet2 in neurons. Viral-mediated neuronal overexpression and RNA interference of Tet2 altered dendritic complexity and synaptic-plasticity-related gene expression in vitro. Overexpression of neuronal Tet2 in adult hippocampus, and loss of Tet2 in adult glutamatergic neurons, resulted in differential hydroxymethylation associated with genes involved in synaptic transmission. Functionally, overexpression of neuronal Tet2 impaired hippocampal-dependent memory, while loss of neuronal Tet2 enhanced memory. Ultimately, these data identify neuronal Tet2 as a molecular target to boost cognitive function.
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Affiliation(s)
- Karishma J B Pratt
- Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, CA 94143, USA; Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA
| | - Jeremy M Shea
- Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, CA 94143, USA
| | - Laura Remesal-Gomez
- Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, CA 94143, USA
| | - Gregor Bieri
- Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, CA 94143, USA
| | - Lucas K Smith
- Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA
| | - Julien Couthouis
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Christopher P Chen
- Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA
| | - Irena J Roy
- Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA
| | - Geraldine Gontier
- Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, CA 94143, USA.
| | - Saul A Villeda
- Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, CA 94143, USA; Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA; Department of Physical Therapy and Rehabilitation Science, San Francisco, CA 94143, USA; Bakar Aging Research Institute, San Francisco, CA 94143, USA.
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13
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Sun J, Wang W, Zhang R, Duan H, Tian X, Xu C, Li X, Zhang D. Multivariate genome-wide association study of depression, cognition, and memory phenotypes and validation analysis identify 12 cross-ethnic variants. Transl Psychiatry 2022; 12:304. [PMID: 35907915 PMCID: PMC9338946 DOI: 10.1038/s41398-022-02074-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 07/15/2022] [Accepted: 07/19/2022] [Indexed: 11/10/2022] Open
Abstract
To date, little is known about the pleiotropic genetic variants among depression, cognition, and memory. The current research aimed to identify the potential pleiotropic single nucleotide polymorphisms (SNPs), genes, and pathways of the three phenotypes by conducting a multivariate genome-wide association study and an additional pleiotropy analysis among Chinese individuals and further validate the top variants in the UK Biobank (UKB). In the discovery phase, the participants were 139 pairs of dizygotic twins from the Qingdao Twins Registry. The genome-wide efficient mixed-model analysis identified 164 SNPs reaching suggestive significance (P < 1 × 10-5). Among them, rs3967317 (P = 1.21 × 10-8) exceeded the genome-wide significance level (P < 5 × 10-8) and was also demonstrated to be associated with depression and memory in pleiotropy analysis, followed by rs9863698, rs3967316, and rs9261381 (P = 7.80 × 10-8-5.68 × 10-7), which were associated with all three phenotypes. After imputation, a total of 457 SNPs reached suggestive significance. The top SNP chr6:24597173 was located in the KIAA0319 gene, which had biased expression in brain tissues. Genes and pathways related to metabolism, immunity, and neuronal systems demonstrated nominal significance (P < 0.05) in gene-based and pathway enrichment analyses. In the validation phase, 12 of the abovementioned SNPs reached the nominal significance level (P < 0.05) in the UKB. Among them, three SNPs were located in the KIAA0319 gene, and four SNPs were identified as significant expression quantitative trait loci in brain tissues. These findings may provide evidence for pleiotropic variants among depression, cognition, and memory and clues for further exploring the shared genetic pathogenesis of depression with Alzheimer's disease.
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Affiliation(s)
- Jing Sun
- Department of Epidemiology and Health Statistics, The School of Public Health of Qingdao University, Qingdao, Shandong Province, China
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weijing Wang
- Department of Epidemiology and Health Statistics, The School of Public Health of Qingdao University, Qingdao, Shandong Province, China
| | - Ronghui Zhang
- Department of Epidemiology and Health Statistics, The School of Public Health of Qingdao University, Qingdao, Shandong Province, China
| | - Haiping Duan
- Qingdao Municipal Center for Disease Control and Prevention, No. 175 Shandong Road, Shibei District, Qingdao, Shandong Province, China
| | - Xiaocao Tian
- Qingdao Municipal Center for Disease Control and Prevention, No. 175 Shandong Road, Shibei District, Qingdao, Shandong Province, China
| | - Chunsheng Xu
- Qingdao Municipal Center for Disease Control and Prevention, No. 175 Shandong Road, Shibei District, Qingdao, Shandong Province, China
| | - Xue Li
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Dongfeng Zhang
- Department of Epidemiology and Health Statistics, The School of Public Health of Qingdao University, Qingdao, Shandong Province, China.
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14
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Jiang L, Greenlaw K, Ciampi A, Canty AJ, Gross J, Turecki G, Greenwood CMT. A Bayesian hierarchical model for improving measurement of 5mC and 5hmC levels: Toward revealing associations between phenotypes and methylation states. Genet Epidemiol 2022; 46:446-462. [PMID: 35753057 DOI: 10.1002/gepi.22489] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 04/20/2022] [Accepted: 05/04/2022] [Indexed: 11/09/2022]
Abstract
5-hydroxymethylcytosine (5hmC) is a methylation state linked with gene regulation, commonly found in cells of the central nervous system. 5hmC is associated with demethylation of cytosines from 5-methylcytosine (5mC) to the unmethylated state. The presence of 5hmC can be inferred by a paired experiment involving bisulfite and oxidation-bisulfite treatments on the same sample, followed by a methylation assay using a platform such as the Illumina Infinium MethylationEPIC BeadChip (EPIC). Existing methods for analysis of the resulting EPIC data are not ideal. Most approaches ignore the correlation between the two experiments and any imprecision associated with DNA damage from the additional treatment. Estimates of 5mC/5hmC levels free from these limitations are desirable to reveal associations between methylation states and phenotypes. We propose a hierarchical Bayesian method called Constrained HYdroxy Methylation Estimation (CHYME) to simultaneously estimate 5mC/5hmC signals as well as any associations between these signals and covariates or phenotypes, while accounting for the potential impact of DNA damage and dependencies induced by the experimental design. Simulations show that CHYME has valid type 1 error and better power than a range of alternative methods, including the popular OxyBS method and linear models on transformed proportions. Other methods we examined suffer from hugely inflated type 1 error for inference on 5hmC proportions. We use CHYME to explore genome-wide associations between 5mC/5hmC levels and cause of death in postmortem prefrontal cortex brain tissue samples. These analyses indicate that CHYME is a useful tool to reveal phenotypic associations with 5mC/5hmC levels.
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Affiliation(s)
- Lai Jiang
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada
| | - Keelin Greenlaw
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada
| | - Antonio Ciampi
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Québec, Canada
| | - Angelo J Canty
- Department of Mathematics and Statistics, McMaster University, Hamilton, Ontario, Canada
| | - Jeffrey Gross
- Department of Psychiatry, Douglas Institute, McGill University, Montréal, Québec, Canada
| | - Gustavo Turecki
- Department of Psychiatry, Douglas Institute, McGill University, Montréal, Québec, Canada
| | - Celia M T Greenwood
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada.,Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Québec, Canada.,Gerald Bronfman Department of Oncology, McGill University, Montréal, Québec, Canada.,Department of Human Genetics, McGill University, Montréal, Québec, Canada
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15
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Sultan FA, Sawaya BE. Gadd45 in Neuronal Development, Function, and Injury. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1360:117-148. [PMID: 35505167 DOI: 10.1007/978-3-030-94804-7_9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The growth arrest and DNA damage-inducible (Gadd) 45 proteins have been associated with numerous cellular mechanisms including cell cycle control, DNA damage sensation and repair, genotoxic stress, neoplasia, and molecular epigenetics. The genes were originally identified in in vitro screens of irradiation- and interleukin-induced transcription and have since been implicated in a host of normal and aberrant central nervous system processes. These include early and postnatal development, injury, cancer, memory, aging, and neurodegenerative and psychiatric disease states. The proteins act through a variety of molecular signaling cascades including the MAPK cascade, cell cycle control mechanisms, histone regulation, and epigenetic DNA demethylation. In this review, we provide a comprehensive discussion of the literature implicating each of the three members of the Gadd45 family in these processes.
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Affiliation(s)
- Faraz A Sultan
- Department of Psychiatry, Rush University, Chicago, IL, USA.
| | - Bassel E Sawaya
- Molecular Studies of Neurodegenerative Diseases Lab, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.,FELS Cancer Institute for Personalized Medicine Institute, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.,Departments of Neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.,Cancer and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.,Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
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16
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New Insights into TETs in Psychiatric Disorders. Int J Mol Sci 2022; 23:ijms23094909. [PMID: 35563298 PMCID: PMC9103987 DOI: 10.3390/ijms23094909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/20/2022] [Accepted: 04/27/2022] [Indexed: 11/21/2022] Open
Abstract
Psychiatric disorders are complex and heterogeneous disorders arising from the interaction of multiple factors based on neurobiology, genetics, culture, and life experience. Increasing evidence indicates that sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Over the past decade, the critical, non-redundant roles of the ten-eleven translocation (TET) family of dioxygenase enzymes have been identified in the brain during developmental and postnatal stages. Specifically, TET-mediated active demethylation, involving the iterative oxidation of 5-methylcytosine to 5-hydroxymethylcytosine and subsequent oxidative derivatives, is dynamically regulated in response to environmental stimuli such as neuronal activity, learning and memory processes, and stressor exposure. Here, we review the progress of studies designed to provide a better understanding of how profiles of TET proteins and 5hmC are powerful mechanisms by which to explain neuronal plasticity and long-term behaviors, and impact transcriptional programs operative in the brain that contribute to psychiatric disorders.
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17
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Present and future antipsychotic drugs: a systematic review of the putative mechanisms of action for efficacy and a critical appraisal under a translational perspective. Pharmacol Res 2022; 176:106078. [PMID: 35026403 DOI: 10.1016/j.phrs.2022.106078] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/23/2021] [Accepted: 01/07/2022] [Indexed: 01/10/2023]
Abstract
Antipsychotics represent the mainstay of schizophrenia pharmacological therapy, and their role has been expanded in the last years to mood disorders treatment. Although introduced in 1952, many years of research were required before an accurate picture of how antipsychotics work began to emerge. Despite the well-recognized characterization of antipsychotics in typical and atypical based on their liability to induce motor adverse events, their main action at dopamine D2R to elicit the "anti-psychotic" effect, as well as the multimodal action at other classes of receptors, their effects on intracellular mechanisms starting with receptor occupancy is still not completely understood. Significant lines of evidence converge on the impact of these compounds on multiple molecular signaling pathways implicated in the regulation of early genes and growth factors, dendritic spine shape, brain inflammation, and immune response, tuning overall the function and architecture of the synapse. Here we present, based on PRISMA approach, a comprehensive and systematic review of the above mechanisms under a translational perspective to disentangle those intracellular actions and signaling that may underline clinically relevant effects and represent potential targets for further innovative strategies in antipsychotic therapy.
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18
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Francisco RD, Fernando V, Norma E, Madai ME, Marcelo B. Glial changes in schizophrenia: Genetic and epigenetic approach. Indian J Psychiatry 2022; 64:3-12. [PMID: 35400734 PMCID: PMC8992743 DOI: 10.4103/indianjpsychiatry.indianjpsychiatry_104_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 10/24/2021] [Accepted: 12/23/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Schizophrenia (SCZ) is a severe mental illness that affects one percent of the population, affecting how people think, feel, and behave. Evidence suggests glial cell alteration and some researchers have found genetic risk loci and epigenetic marks that may regulate glia-related genes implicated in SCZ. AIM The aim of this study is to identify genetic and epigenetic changes that have been reported in glial cells or glial-associated genes in SCZ. MATERIALS AND METHODS We searched the articles from PubMed, PubMed Central, Medline, Medscape, and Embase databases up to December 2020 to identify relevant peer-reviewed articles in English. The titles and abstracts were screened to eliminate irrelevant citations. RESULTS Twenty-four original articles were included in the review. Studies were categorized into the following four thematic via: (1) oligodendrocytes, (2) microglia, (3) astrocytes, and (4) perspectives. CONCLUSION This study is the first of its kind to review research on genetic variants and epigenetic modifications associated with glia-related genes implicated in SCZ. Epigenetic evidence is considerably less than genetic evidence in this field. Understanding the pathways of some risk genes and their genetic and epigenetic regulation allows us to understand and find potential targets for future interventions in this mental illness.
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Affiliation(s)
- Ramos Daniel Francisco
- Faculty of Chemical Sciences, Juarez University of the State of Durango, Durango, Mexico
| | - Vazquez Fernando
- Faculty of Chemical Sciences, Juarez University of the State of Durango, Durango, Mexico.,Research Unit, General Hospital 450, Durango, Mexico
| | - Estrada Norma
- Faculty of Chemical Sciences, Juarez University of the State of Durango, Durango, Mexico
| | - Méndez Edna Madai
- Scientific Research Institute, Juarez University of the State of Durango, Durango, Mexico
| | - Barraza Marcelo
- Faculty of Chemical Sciences, Juarez University of the State of Durango, Durango, Mexico
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19
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Srivastava A, Dada O, Qian J, Al-Chalabi N, Fatemi AB, Gerretsen P, Graff A, De Luca V. Epigenetics of Schizophrenia. Psychiatry Res 2021; 305:114218. [PMID: 34638051 DOI: 10.1016/j.psychres.2021.114218] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 09/07/2021] [Accepted: 09/20/2021] [Indexed: 12/31/2022]
Abstract
Schizophrenia (SCZ) is a chronic psychotic disorder that contributes significantly to disability, affecting behavior, thought, and cognition. It has long been known that there is a heritable component to schizophrenia; studies in both the pre-genomic and post-genomic era, however, have failed to elucidate fully the genetic basis for this complex disease. Epigenetic processes - broadly, those which contribute to changes in gene expression without altering the genetic code itself - may help to understand better the mechanisms leading to development of SCZ. The objective of this review is to synthesize current knowledge of the epigenetic mechanisms involved in schizophrenia. Specifically, DNA methylation studies in both peripheral and post-mortem brain samples in SCZ are reviewed, as are epigenetic mechanisms including histone modification. The promising role of non-coding RNA including micro-RNA (miRNA) and its role as a potential diagnostic and therapeutic biomarker is outlined, as are epigenetic age acceleration and telomere shortening. Finally, we discuss limitations in current knowledge and propose future research directions.
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Affiliation(s)
| | | | | | | | | | | | - Ariel Graff
- Department of Psychiatry, University of Toronto
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20
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Liu W, Wu G, Xiong F, Chen Y. Advances in the DNA methylation hydroxylase TET1. Biomark Res 2021; 9:76. [PMID: 34656178 PMCID: PMC8520278 DOI: 10.1186/s40364-021-00331-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 10/03/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The ten-eleven translocation 1 (TET1) protein is a 5-methylcytosine hydroxylase that belongs to the TET protein family of human α-ketoglutarate oxygenases. TET1 recognizes and binds to regions of high genomic 5'-CpG-3' dinucleotide density, such as CpG islands, initiates the DNA demethylation program, and maintains DNA methylation and demethylation balance to maintain genomic methylation homeostasis and achieve epigenetic regulation. This article reviews the recent research progress of TET1 in the mechanism of demethylation, stem cells and immunity, various malignant tumours and other clinical diseases. CONCLUSION TET1 acts as a key factor mediating demethylation, the mechanism of which still remains to be investigated in detail. TET1 is also critical in maintaining the differentiation pluripotency of embryonic stem cells and plays anti- or oncogenic roles in combination with different signalling pathways in different tumours. In certain tumours, its role is still controversial. In addition, the noncatalytic activity of TET1 has gradually attracted attention and has become a new direction of research in recent years.
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Affiliation(s)
- Wenzheng Liu
- Department of Biliary and Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
| | - Guanhua Wu
- Department of Biliary and Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
| | - Fei Xiong
- Department of Biliary and Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
| | - Yongjun Chen
- Department of Biliary and Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China.
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21
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Saxena S, Choudhury S, Maroju PA, Anne A, Kumar L, Mohan KN. Dysregulation of schizophrenia-associated genes and genome-wide hypomethylation in neurons overexpressing DNMT1. Epigenomics 2021; 13:1539-1555. [PMID: 34647491 DOI: 10.2217/epi-2021-0133] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To study the effects of DNMT1 overexpression on transcript levels of genes dysregulated in schizophrenia and on genome-wide methylation patterns. Materials & methods: Transcriptome and DNA methylome comparisons were made between R1 (wild-type) and Dnmt1tet/tet mouse embryonic stem cells and neurons overexpressing DNMT1. Genes dysregulated in both Dnmt1tet/tet cells and schizophrenia patients were studied further. Results & conclusions: About 50% of dysregulated genes in patients also showed altered transcript levels in Tet/Tet neurons in a DNA methylation-independent manner. These neurons unexpectedly showed genome-wide hypomethylation, increased transcript levels of Tet1 and Apobec 1-3 genes and increased activity and copy number of LINE-1 elements. The observed similarities between Tet/Tet neurons and schizophrenia brain samples reinforce DNMT1 overexpression as a risk factor.
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Affiliation(s)
- Sonal Saxena
- Department of Biological Sciences, Birla Institute of Technology & Science, Pilani, Hyderabad, 500078, India
| | - Sumana Choudhury
- Department of Biological Sciences, Birla Institute of Technology & Science, Pilani, Hyderabad, 500078, India.,Centre for Human Disease Research, Birla Institute of Technology & Science, Pilani, Hyderabad, 500078, India
| | - Pranay Amruth Maroju
- Department of Biological Sciences, Birla Institute of Technology & Science, Pilani, Hyderabad, 500078, India
| | - Anuhya Anne
- Department of Biological Sciences, Birla Institute of Technology & Science, Pilani, Hyderabad, 500078, India.,Centre for Human Disease Research, Birla Institute of Technology & Science, Pilani, Hyderabad, 500078, India
| | - Lov Kumar
- Computer Science & Information Systems, Birla Institute of Technology & Science, Pilani, Hyderabad, 500078, India
| | - Kommu Naga Mohan
- Department of Biological Sciences, Birla Institute of Technology & Science, Pilani, Hyderabad, 500078, India.,Centre for Human Disease Research, Birla Institute of Technology & Science, Pilani, Hyderabad, 500078, India
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22
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Sershen H, Guidotti A, Auta J, Drnevich J, Grayson DR, Veldic M, Meyers J, Youseff M, Zhubi A, Faurot K, Wu R, Zhao J, Jin H, Lajtha A, Davis JM, Smith RC. Gene Expression Of Methylation Cycle And Related Genes In Lymphocytes And Brain Of Patients With Schizophrenia And Non-Psychotic Controls. Biomark Neuropsychiatry 2021; 5. [PMID: 34368786 DOI: 10.1016/j.bionps.2021.100038] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Some of the biochemical abnormalities underlying schizophrenia, involve differences in methylation and methylating enzymes, as well as other related target genes. We present results of a study of differences in mRNA expression in peripheral blood lymphocytes (PBLs) and post-mortem brains of chronic schizophrenics (CSZ) and non-psychotic controls (NPC), emphasizing the differential effects of sex and antipsychotic drug treatment on mRNA findings. We studied mRNA expression in lymphocytes of 61 CSZ and 49 NPC subjects using qPCR assays with TaqMan probes to assess levels of DNMT, TET, GABAergic, NR3C1, BDNF mRNAs, and several additional targets identified in a recent RNA sequence analysis. In parallel we studied DNMT1 and GAD67 in samples of brain tissues from 19 CSZ, 26 NPC. In PBLs DNMT1 and DNMT3A mRNA levels were significantly higher in male CSZ vs NPC. No significant differences were detected in females. The GAD1, NR3C1 and CNTNAP2 mRNA levels were significantly higher in CSZ than NPC. In CSZ patients treated with clozapine, GAD-1 related, CNTNAP2, and IMPA2 mRNAs were significantly higher than in CSZ subjects not treated with clozapine. Differences between CSZ vs NPC in these mRNAs was primarily attributable to the clozapine treatment. In the brain samples, DNMT1 was significantly higher and GAD67 was significantly lower in CSZ than in NPC, but there were no significant sex differences in diagnostic effects. These findings highlight the importance of considering sex and drug treatment effects in assessing the substantive significance of differences in mRNAs between CSZ and NPC.
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Affiliation(s)
- Henry Sershen
- Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA.,NYU Langone Medical Center, Department of Psychiatry, New York, New York, USA
| | - Alessandro Guidotti
- Psychiatric Institute University of Illinois, Department of Psychiatry, Chicago, Illinois, USA
| | - James Auta
- Psychiatric Institute University of Illinois, Department of Psychiatry, Chicago, Illinois, USA
| | - Jenny Drnevich
- High Performance Biological Computing group and the Roy J. Carver Biotechnology Center University of Illinois, Urbana, USA
| | - Dennis R Grayson
- Psychiatric Institute University of Illinois, Department of Psychiatry, Chicago, Illinois, USA
| | - Marin Veldic
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota
| | - Jordan Meyers
- Oregon Health and Science University, Portland, Oregon, USA
| | - Mary Youseff
- Harlem Hospital, Department of Psychiatry, New York, NY, US
| | - Adrian Zhubi
- Psychiatric Institute University of Illinois, Department of Psychiatry, Chicago, Illinois, USA
| | - Keturah Faurot
- Department of Physical Medicine & Rehabilitation, University of North Carolina at Chapel Hill, North Carolina
| | - Renrong Wu
- Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, Hunan, and Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jingping Zhao
- Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, Hunan, and Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hua Jin
- University of California San Diego, Department of Psychiatry, San Diego, and VA San Diego Healthcare System, San Diego, California, USA
| | - Abel Lajtha
- Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA.,NYU Langone Medical Center, Department of Psychiatry, New York, New York, USA
| | - John M Davis
- Psychiatric Institute University of Illinois, Department of Psychiatry, Chicago, Illinois, USA
| | - Robert C Smith
- Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA.,NYU Langone Medical Center, Department of Psychiatry, New York, New York, USA
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23
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Dick A, Chen A. The role of TET proteins in stress-induced neuroepigenetic and behavioural adaptations. Neurobiol Stress 2021; 15:100352. [PMID: 34189192 PMCID: PMC8220100 DOI: 10.1016/j.ynstr.2021.100352] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 05/21/2021] [Accepted: 06/05/2021] [Indexed: 12/27/2022] Open
Abstract
Over the past decade, critical, non-redundant roles of the ten-eleven translocation (TET) family of dioxygenase enzymes have been identified in the brain during developmental and postnatal stages. Specifically, TET-mediated active demethylation, involving the iterative oxidation of 5-methylcytosine to 5-hydroxymethylcytosine and subsequent oxidative derivatives, is dynamically regulated in response to environmental stimuli such as neuronal activity, learning and memory processes, and stressor exposure. Such changes may therefore perpetuate stable and dynamic transcriptional patterns within neuronal populations required for neuroplasticity and behavioural adaptation. In this review, we will highlight recent evidence supporting a role of TET protein function and active demethylation in stress-induced neuroepigenetic and behavioural adaptations. We further explore potential mechanisms by which TET proteins may mediate both the basal and pathological embedding of stressful life experiences within the brain of relevance to stress-related psychiatric disorders.
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Affiliation(s)
- Alec Dick
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
- Corresponding author.
| | - Alon Chen
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
- The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
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24
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Chaudhury S. Epigenetic regulation in Autism spectrum disorder. AIMS GENETICS 2021. [DOI: 10.3934/genet.2016.4.292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by an impaired social communication skill and often results in repetitive, stereotyped behavior which is observed in children during the first few years of life. Other characteristic of this disorder includes language disabilities, difficulties in sensory integration, lack of reciprocal interactions and in some cases, cognitive delays. One percentage of the general population is affected by ASD and is four times more common in boys than girls. There are hundreds of genes, which has been identified to be associated with ASD etiology. However it remains difficult to comprehend our understanding in defining the genetic architecture necessary for complete exposition of its pathophysiology. Seeing the complexity of the disease, it is important to adopt a multidisciplinary approach which should not only focus on the “genetics” of autism but also on epigenetics, transcriptomics, immune system disruption and environmental factors that could all impact the pathogenesis of the disease. As environmental factors also play a key role in regulating the trigger of ASD, the role of chromatin remodeling and DNA methylation has started to emerge. Such epigenetic modifications directly link molecular regulatory pathways and environmental factors, which might be able to explain some aspects of complex disorders like ASD. The present review will focus on the role of epigenetic regulation in defining the underlying cause for ASD.
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Affiliation(s)
- Sraboni Chaudhury
- Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI-48109, USA
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25
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Antunes C, Da Silva JD, Guerra-Gomes S, Alves ND, Ferreira F, Loureiro-Campos E, Branco MR, Sousa N, Reik W, Pinto L, Marques CJ. Tet3 ablation in adult brain neurons increases anxiety-like behavior and regulates cognitive function in mice. Mol Psychiatry 2021; 26:1445-1457. [PMID: 32103150 DOI: 10.1038/s41380-020-0695-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 01/16/2020] [Accepted: 02/18/2020] [Indexed: 01/25/2023]
Abstract
TET3 is a member of the ten-eleven translocation (TET) family of enzymes which oxidize 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). Tet3 is highly expressed in the brain, where 5hmC levels are most abundant. In adult mice, we observed that TET3 is present in mature neurons and oligodendrocytes but is absent in astrocytes. To investigate the function of TET3 in adult postmitotic neurons, we crossed Tet3 floxed mice with a neuronal Cre-expressing mouse line, Camk2a-CreERT2, obtaining a Tet3 conditional KO (cKO) mouse line. Ablation of Tet3 in adult mature neurons resulted in increased anxiety-like behavior with concomitant hypercorticalism, and impaired hippocampal-dependent spatial orientation. Transcriptome and gene-specific expression analysis of the hippocampus showed dysregulation of genes involved in glucocorticoid signaling pathway (HPA axis) in the ventral hippocampus, whereas upregulation of immediate early genes was observed in both dorsal and ventral hippocampal areas. In addition, Tet3 cKO mice exhibit increased dendritic spine maturation in the ventral CA1 hippocampal subregion. Based on these observations, we suggest that TET3 is involved in molecular alterations that govern hippocampal-dependent functions. These results reveal a critical role for epigenetic modifications in modulating brain functions, opening new insights into the molecular basis of neurological disorders.
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Affiliation(s)
- Cláudia Antunes
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, 4710-057, Braga/Guimarães, Portugal
| | - Jorge D Da Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, 4710-057, Braga/Guimarães, Portugal
| | - Sónia Guerra-Gomes
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, 4710-057, Braga/Guimarães, Portugal
| | - Nuno D Alves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, 4710-057, Braga/Guimarães, Portugal
| | - Fábio Ferreira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, 4710-057, Braga/Guimarães, Portugal
| | - Eduardo Loureiro-Campos
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, 4710-057, Braga/Guimarães, Portugal
| | - Miguel R Branco
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK
| | - Nuno Sousa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, 4710-057, Braga/Guimarães, Portugal
| | - Wolf Reik
- Epigenetics Programme, The Babraham Institute, Cambridge, CB22 3AT, UK.,The Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK
| | - Luísa Pinto
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal. .,ICVS/3B's-PT Government Associate Laboratory, 4710-057, Braga/Guimarães, Portugal.
| | - C Joana Marques
- Department of Genetics, Faculty of Medicine, University of Porto (FMUP), 4200-319, Porto, Portugal. .,i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal.
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26
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Richetto J, Meyer U. Epigenetic Modifications in Schizophrenia and Related Disorders: Molecular Scars of Environmental Exposures and Source of Phenotypic Variability. Biol Psychiatry 2021; 89:215-226. [PMID: 32381277 DOI: 10.1016/j.biopsych.2020.03.008] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 02/19/2020] [Accepted: 03/16/2020] [Indexed: 12/18/2022]
Abstract
Epigenetic modifications are increasingly recognized to play a role in the etiology and pathophysiology of schizophrenia and other psychiatric disorders with developmental origins. Here, we summarize clinical and preclinical findings of epigenetic alterations in schizophrenia and relevant disease models and discuss their putative origin. Recent findings suggest that certain schizophrenia risk loci can influence stochastic variation in gene expression through epigenetic processes, highlighting the intricate interaction between genetic and epigenetic control of neurodevelopmental trajectories. In addition, a substantial portion of epigenetic alterations in schizophrenia and related disorders may be acquired through environmental factors and may be manifested as molecular "scars." Some of these scars can influence brain functions throughout the entire lifespan and may even be transmitted across generations via epigenetic germline inheritance. Epigenetic modifications, whether caused by genetic or environmental factors, are plausible molecular sources of phenotypic heterogeneity and offer a target for therapeutic interventions. The further elucidation of epigenetic modifications thus may increase our knowledge regarding schizophrenia's heterogeneous etiology and pathophysiology and, in the long term, may advance personalized treatments through the use of biomarker-guided epigenetic interventions.
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Affiliation(s)
- Juliet Richetto
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, and Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
| | - Urs Meyer
- Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, and Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
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27
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Yang M, Barrios J, Yan J, Zhao W, Yuan S, Dong E, Ai X. Causal roles of stress kinase JNK2 in DNA methylation and binge alcohol withdrawal-evoked behavioral deficits. Pharmacol Res 2021; 164:105375. [PMID: 33316384 PMCID: PMC7867628 DOI: 10.1016/j.phrs.2020.105375] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/20/2020] [Accepted: 12/06/2020] [Indexed: 11/27/2022]
Abstract
Excessive binge alcohol intake is a common drinking pattern in humans, especially during holidays. Cessation of the binge drinking often leads to aberrant withdrawal behaviors, as well as serious heart rhythm abnormalities (clinically diagnosed as Holiday Heart Syndrome (HHS)). In our HHS mouse model with well-characterized binge alcohol withdrawal (BAW)-induced heart phenotypes, BAW leads to anxiety-like behaviors and cognitive impairment. We have previously reported that stress-activated c-Jun NH(2)-terminal kinase (JNK) plays a causal role in BAW-induced heart phenotypes. In the HHS brain, we found that activation of JNK2 (but not JNK1 and JNK3) in the prefrontal cortex (PFC), but not hippocampus and amygdala, led to anxiety-like behaviors and impaired cognition. DNA methylation mediated by a crucial DNA methylation enzyme, DNA methyltransferase1 (DNMT1), is known to be critical in alcohol-associated behavioral deficits. In HHS mice, JNK2 in the PFC (but not hippocampus and amygdala) causally enhanced total genomic DNA methylation via increased DNMT1 expression, which was regulated by enhanced binding of JNK downstream transcriptional factor c-JUN to the DNMT1 promoter. JNK2-specific inhibition either by an inhibitor JNK2I or JNK2 knockout completely offset c-JUN-regulated DNMT1 upregulation and restored the level of DNA methylation in HHS PFC to the baseline levels seen in sham controls. Strikingly, either JNK2-specific inhibition or genetic JNK2 depletion or DNMT1 inhibition (by an inhibitor 5-Azacytidine) completely abolished BAW-evoked behavioral deficits. In conclusion, our studies revealed a novel mechanism by which JNK2 drives BAW-evoked behavioral deficits through a DNMT1-regulated DNA hypermethylation. JNK2 could be a novel therapeutic target for alcohol withdrawal treatment and/or prevention.
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Affiliation(s)
- Mei Yang
- Department of Physiology & Biophysics, Rush University Medical Center, Chicago, IL, 60607, USA
| | - Jasson Barrios
- Department of Physiology & Biophysics, Rush University Medical Center, Chicago, IL, 60607, USA
| | - Jiajie Yan
- Department of Physiology & Biophysics, Rush University Medical Center, Chicago, IL, 60607, USA
| | - Weiwei Zhao
- Department of Physiology & Biophysics, Rush University Medical Center, Chicago, IL, 60607, USA
| | - Shengtao Yuan
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China
| | - Erbo Dong
- Center for Alcohol Research in Epigenetics, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, IL, 60612, USA.
| | - Xun Ai
- Department of Physiology & Biophysics, Rush University Medical Center, Chicago, IL, 60607, USA.
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28
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Greer CB, Wright J, Weiss JD, Lazarenko RM, Moran SP, Zhu J, Chronister KS, Jin AY, Kennedy AJ, Sweatt JD, Kaas GA. Tet1 Isoforms Differentially Regulate Gene Expression, Synaptic Transmission, and Memory in the Mammalian Brain. J Neurosci 2021; 41:578-593. [PMID: 33262245 PMCID: PMC7842754 DOI: 10.1523/jneurosci.1821-20.2020] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 09/28/2020] [Accepted: 11/02/2020] [Indexed: 12/22/2022] Open
Abstract
The dynamic regulation of DNA methylation in postmitotic neurons is necessary for memory formation and other adaptive behaviors. Ten-eleven translocation 1 (TET1) plays a part in these processes by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby initiating active DNA demethylation. However, attempts to pinpoint its exact role in the nervous system have been hindered by contradictory findings, perhaps due in part, to a recent discovery that two isoforms of the Tet1 gene are differentially expressed from early development into adulthood. Here, we demonstrate that both the shorter transcript (Tet1S ) encoding an N-terminally truncated TET1 protein and a full-length Tet1 (Tet1FL ) transcript encoding canonical TET1 are co-expressed in the adult mouse brain. We show that Tet1S is the predominantly expressed isoform and is highly enriched in neurons, whereas Tet1FL is generally expressed at lower levels and more abundant in glia, suggesting their roles are at least partially cell type-specific. Using viral-mediated, isoform and neuron-specific molecular tools, we find that the individual repression of each transcript leads to the dysregulation of unique gene ensembles and contrasting changes in basal synaptic transmission. In addition, Tet1S repression enhances, while Tet1FL impairs, hippocampal-dependent memory in male mice. Together, our findings demonstrate that each Tet1 isoform serves a distinct role in the mammalian brain.SIGNIFICANCE STATEMENT In the brain, activity-dependent changes in gene expression are required for the formation of long-term memories. DNA methylation plays an essential role in orchestrating these learning-induced transcriptional programs by influencing chromatin accessibility and transcription factor binding. Once thought of as a stable epigenetic mark, DNA methylation is now known to be impermanent and dynamically regulated, driving neuroplasticity in the brain. We found that Tet1, a member of the ten-eleven translocation (TET) family of enzymes that mediates removal of DNA methyl marks, is expressed as two separate isoforms in the adult mouse brain and that each differentially regulates gene expression, synaptic transmission and memory formation. Together, our findings demonstrate that each Tet1 isoform serves a distinct role in the CNS.
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Affiliation(s)
- C B Greer
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232
| | - J Wright
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232
| | - J D Weiss
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232
| | - R M Lazarenko
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232
| | - S P Moran
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232
| | - J Zhu
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232
| | - K S Chronister
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232
| | - A Y Jin
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232
| | - A J Kennedy
- Department of Chemistry, Bates College, Lewiston, Maine 04240
| | - J D Sweatt
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232
| | - G A Kaas
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232
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29
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Reiner BC, Doyle GA, Weller AE, Levinson RN, Rao AM, Davila Perea E, Namoglu E, Pigeon A, Arauco-Shapiro G, Weickert CS, Turecki G, Crist RC, Berrettini WH. Inherited L1 Retrotransposon Insertions Associated With Risk for Schizophrenia and Bipolar Disorder. SCHIZOPHRENIA BULLETIN OPEN 2021; 2:sgab031. [PMID: 34901866 PMCID: PMC8650070 DOI: 10.1093/schizbullopen/sgab031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Studies of the genetic heritability of schizophrenia and bipolar disorder examining single nucleotide polymorphisms (SNPs) and copy number variations have failed to explain a large portion of the genetic liability, resulting in substantial missing heritability. Long interspersed element 1 (L1) retrotransposons are a type of inherited polymorphic variant that may be associated with risk for schizophrenia and bipolar disorder. We performed REBELseq, a genome wide assay for L1 sequences, on DNA from male and female persons with schizophrenia and controls (n = 63 each) to identify inherited L1 insertions and validated priority insertions. L1 insertions of interest were genotyped in DNA from a replication cohort of persons with schizophrenia, bipolar disorder, and controls (n = 2268 each) to examine differences in carrier frequencies. We identified an inherited L1 insertion in ARHGAP24 and a quadallelic SNP (rs74169643) inside an L1 insertion in SNTG2 that are associated with risk for developing schizophrenia and bipolar disorder (all odds ratios ~1.2). Pathway analysis identified 15 gene ontologies that were differentially affected by L1 burden, including multiple ontologies related to glutamatergic signaling and immune function, which have been previously associated with schizophrenia. These findings provide further evidence supporting the role of inherited repetitive genetic elements in the heritability of psychiatric disorders.
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Affiliation(s)
- Benjamin C Reiner
- Molecular and Neural Basis of Psychiatric Disease Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Glenn A Doyle
- Molecular and Neural Basis of Psychiatric Disease Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Andrew E Weller
- Molecular and Neural Basis of Psychiatric Disease Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Rachel N Levinson
- Molecular and Neural Basis of Psychiatric Disease Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Aditya M Rao
- Molecular and Neural Basis of Psychiatric Disease Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Emilie Davila Perea
- Molecular and Neural Basis of Psychiatric Disease Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Esin Namoglu
- Molecular and Neural Basis of Psychiatric Disease Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Alicia Pigeon
- Molecular and Neural Basis of Psychiatric Disease Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Gabriella Arauco-Shapiro
- Molecular and Neural Basis of Psychiatric Disease Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Cyndi Shannon Weickert
- Schizophrenia Research Laboratory, Neuroscience Research Australia & School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
- Department of Neuroscience & Physiology, Upstate Medical University, Syracuse, NY, USA
| | - Gustavo Turecki
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Canada
| | - Richard C Crist
- Molecular and Neural Basis of Psychiatric Disease Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Wade H Berrettini
- Molecular and Neural Basis of Psychiatric Disease Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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30
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Miyanishi H, Uno K, Iwata M, Kikuchi Y, Yamamori H, Yasuda Y, Ohi K, Hashimoto R, Hattori K, Yoshida S, Goto YI, Sumiyoshi T, Nitta A. Investigating DNA Methylation of SHATI/NAT8L Promoter Sites in Blood of Unmedicated Patients with Major Depressive Disorder. Biol Pharm Bull 2020; 43:1067-1072. [PMID: 32612069 DOI: 10.1248/bpb.b19-01099] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Major depressive disorder (MDD) is one of the most common psychiatric diseases. However, early detection and diagnosis of MDD is difficult, largely because there is no known biomarker or objective diagnostic examination, and its diagnosis is instead based on a clinical interview. The aim of this study was to develop a novel diagnostic tool using DNA methylation as a blood biomarker. We sought to determine whether unmedicated patients with MDD showed significant differences in DNA methylation in the promoter region of the SHATI/N-acetyltransferase 8 like (SHATI/NAT8L) gene compared to healthy controls. Sixty participants with MDD were recruited from all over Japan. They were diagnosed and assessed by at least two trained psychiatrists according to DSM-5 criteria. DNA was extracted from peripheral blood. We then assessed DNA methylation of the SHATI/NAT8L promoter regions in patients with MDD by pyrosequencing. Methylation levels of the SHATI/NAT8L promoter region at CpG sites in peripheral blood from unmedicated patients were significantly higher than in healthy controls. In contrast, medicated patients with MDD showed significantly lower methylation levels in the same region compared to healthy controls. Since previous studies of DNA methylation in MDD only assessed medicated patients, the methylation status of the SHATI/NAT8L promoter region in unmedicated patients presented herein may prove useful for the diagnosis of MDD. To our knowledge, this is the first attempt to measure methylation of the SHATI/NAT8L gene in drug-naïve patients with psychiatric diseases. Based on our findings, methylation of SHATI/NAT8L DNA might be a diagnostic biomarker of MDD.
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Affiliation(s)
- Hajime Miyanishi
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, University of Toyama
| | - Kyosuke Uno
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, University of Toyama.,Laboratory of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University
| | - Mina Iwata
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, University of Toyama
| | - Yuu Kikuchi
- Department of Psychiatry, Osaka University Graduate School of Medicine
| | - Hidenaga Yamamori
- Department of Psychiatry, Osaka University Graduate School of Medicine
| | - Yuka Yasuda
- Department of Psychiatry, Osaka University Graduate School of Medicine
| | - Kazutaka Ohi
- Department of Psychiatry, Osaka University Graduate School of Medicine
| | - Ryota Hashimoto
- Department of Psychiatry, Osaka University Graduate School of Medicine.,Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry
| | - Kotaro Hattori
- Medical Genome Center, National Center of Neurology and Psychiatry
| | - Sumiko Yoshida
- Medical Genome Center, National Center of Neurology and Psychiatry
| | - Yu-Ichi Goto
- Department of Preventive Intervention, National Institute of Mental Health, National Center of Neurology and Psychiatry
| | - Tomiki Sumiyoshi
- Department of Preventive Intervention, National Institute of Mental Health, National Center of Neurology and Psychiatry
| | - Atsumi Nitta
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, University of Toyama
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31
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Fu X, Wang J, Du J, Sun J, Baranova A, Zhang F. BDNF Gene's Role in Schizophrenia: From Risk Allele to Methylation Implications. Front Psychiatry 2020; 11:564277. [PMID: 33384622 PMCID: PMC7769935 DOI: 10.3389/fpsyt.2020.564277] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 11/25/2020] [Indexed: 11/24/2022] Open
Abstract
Background: Schizophrenia (SZ) is a severe chronic mental disorder with complex genetic mechanisms. Brain-derived neurotrophic factor (BDNF) is one of promising candidate genes for SZ, and rs6265 is a non-synonymous single nucleotide polymorphism (SNP) in BDNF. Methods: In this study, we performed a case-control association study of rs6265 in a cohort of Han Chinese population from eastern China, including 1,407 SZ patients and 1,136 healthy controls; and carried out a cis-mQTL (Methylation Quantitative Trait Loci) analysis for BDNF rs6265. Results: We found a positive association of rs6265 with SZ (P = 0.037), with the minor allele (A) of rs6265 conferring a protecting effect for SZ (OR = 0.89). Furthermore, cis-mQTL analysis indicates that rs6265 is associated with several methylation loci surrounding BDNF. Conclusions: Together, our findings provide further evidence to support the involvement of BDNF gene in the genesis of SZ.
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Affiliation(s)
- Xiaoqian Fu
- Department of Clinical Psychology, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, China
| | - Jun Wang
- Department of Psychiatry, Wuxi Mental Health Center of Nanjing Medical University, Wuxi, China
| | - Jianbin Du
- Department of Psychiatry, Wuxi Mental Health Center of Nanjing Medical University, Wuxi, China
| | - Jing Sun
- Department of Psychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
| | - Ancha Baranova
- School of Systems Biology, George Mason University, Fairfax, VA, United States
- Research Centre for Medical Genetics, Moscow, Russia
| | - Fuquan Zhang
- Department of Psychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
- Institute of Neuropsychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China
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32
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Dong E, Pandey SC. Prenatal stress induced chromatin remodeling and risk of psychopathology in adulthood. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2020; 156:185-215. [PMID: 33461663 PMCID: PMC7864549 DOI: 10.1016/bs.irn.2020.08.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
New insights into the pathophysiology of psychiatric disorders suggest the existence of a complex interplay between genetics and environment. This notion is supported by evidence suggesting that exposure to stress during pregnancy exerts profound effects on the neurodevelopment and behavior of the offspring and predisposes them to psychiatric disorders later in life. Accumulated evidence suggests that vulnerability to psychiatric disorders may result from permanent negative effects of long-term changes in synaptic plasticity due to altered epigenetic mechanisms (histone modifications and DNA methylation) that lead to condensed chromatin architecture, thereby decreasing the expression of candidate genes during early brain development. In this chapter, we have summarized the literature of clinical studies on psychiatric disorders induced by maternal stress during pregnancy. We also discussed the epigenetic alterations of gene regulations induced by prenatal stress. Because the clinical manifestations of psychiatric disorders are complex, it is obvious that the biological progression of these diseases cannot be studied only in postmortem brains of patients and the use of animal models is required. Therefore, in this chapter, we have introduced a well-established mouse model of prenatal stress (PRS) generated in restrained pregnant dams. The behavioral phenotypes of the offspring (PRS mice) born to the stressed dam and underlying epigenetic changes in key molecules related to synaptic activity were described and highlighted. PRS mice may serve as a useful model for investigating the pathogenesis of psychiatric disorders and may be a useful tool for screening for the potential compounds that may normalize aberrant epigenetic mechanisms induced by prenatal stress.
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Affiliation(s)
- Erbo Dong
- Center for Alcohol Research in Epigenetics, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States.
| | - Subhash C Pandey
- Center for Alcohol Research in Epigenetics, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States; Jesse Brown VA Medical Center, Chicago, IL, United States
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33
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Linde J, Zimmer-Bensch G. DNA Methylation-Dependent Dysregulation of GABAergic Interneuron Functionality in Neuropsychiatric Diseases. Front Neurosci 2020; 14:586133. [PMID: 33041771 PMCID: PMC7525021 DOI: 10.3389/fnins.2020.586133] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 08/25/2020] [Indexed: 12/30/2022] Open
Abstract
Neuropsychiatric diseases, such as mood disorders, schizophrenia, and autism, represent multifactorial disorders, differing in causes, disease onset, severity, and symptoms. A common feature of numerous neuropsychiatric conditions are defects in the cortical inhibitory GABAergic system. The balance of excitation and inhibition is fundamental for proper and efficient information processing in the cerebral cortex. Thus, altered inhibition is suggested to account for pathological symptoms like cognitive impairments and dysfunctional multisensory integration. While it became apparent that most of these diseases have a clear genetic component, environmental influences emerged as an impact of disease manifestation, onset, and severity. Epigenetic mechanisms of transcriptional control, such as DNA methylation, are known to be responsive to external stimuli, and are suspected to be implicated in the functional impairments of GABAergic interneurons, and hence, the pathophysiology of neuropsychiatric diseases. Here, we provide an overview about the multifaceted functional implications of DNA methylation and DNA methyltransferases in cortical interneuron development and function in health and disease. Apart from the regulation of gamma-aminobutyric acid-related genes and genes relevant for interneuron development, we discuss the role of DNA methylation-dependent regulation of synaptic transmission by the modulation of endocytosis-related genes as potential pathophysiological mechanisms underlying neuropsychiatric conditions. Deciphering the hierarchy and mechanisms of changes in epigenetic signatures is crucial to develop effective strategies for treatment and prevention.
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Affiliation(s)
- Jenice Linde
- Division of Functional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, Aachen, Germany.,Research Training Group 2416 MultiSenses - MultiScales, RWTH Aachen University, Aachen, Germany
| | - Geraldine Zimmer-Bensch
- Division of Functional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, Aachen, Germany.,Research Training Group 2416 MultiSenses - MultiScales, RWTH Aachen University, Aachen, Germany
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34
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Skeletal muscle DNA methylation modifications and psychopharmacologic treatment in bipolar disorder. Eur Neuropsychopharmacol 2019; 29:1365-1373. [PMID: 31635791 PMCID: PMC6924624 DOI: 10.1016/j.euroneuro.2019.10.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 07/29/2019] [Accepted: 10/01/2019] [Indexed: 01/08/2023]
Abstract
Both severe mental illness and atypical antipsychotics have been independently associated with insulin resistance and weight gain. Altered regulation of skeletal muscle DNA methylation may play a role. We aimed to evaluate DNA methylation modifications in human skeletal muscle samples to further understand its potential role in the metabolic burden observed in psychiatric patients and psychopharmacologic treatment. Subjects were included in our study if they had a bipolar diagnosis and were currently treated with a mood stabilizer or atypical antipsychotic. A healthy control group free of psychiatric or physical disease was also included for comparisons. Anthropometric, BMI and hemoglobin A1C (HbA1C%) were measured. Fasting skeletal muscle biopsies were obtained and methylation levels of 5-methycytosine (5-mC), 5-hydroxymethylcytosine (5-hmC) and 5-formylcytosine (5-fC) were measured. Skeletal muscle global methylation of 5-mC and 5-fC were significantly higher in bipolar subjects compared to healthy controls. 5-mC was significantly higher in the AAP group compared to the mood stabilizer group. Significant correlations were observed between 5-fC methylation and HbA1C%. Our findings suggest that psychiatric disease and treatment may influence some methylation measures in the skeletal muscle of patients with bipolar disorder, which may be further influenced by medication treatment.
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35
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Cook IA, Congdon E, Krantz DE, Hunter AM, Coppola G, Hamilton SP, Leuchter AF. Time Course of Changes in Peripheral Blood Gene Expression During Medication Treatment for Major Depressive Disorder. Front Genet 2019; 10:870. [PMID: 31620172 PMCID: PMC6760033 DOI: 10.3389/fgene.2019.00870] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 08/20/2019] [Indexed: 12/11/2022] Open
Abstract
Changes in gene expression (GE) during antidepressant treatment may increase understanding of the action of antidepressant medications and serve as biomarkers of efficacy. GE changes in peripheral blood are desirable because they can be assessed easily on multiple occasions during treatment. We report here on GE changes in 68 individuals who were treated for 8 weeks with either escitalopram alone, or escitalopram followed by bupropion. GE changes were assessed after 1, 2, and 8 weeks of treatment, with significant changes observed in 156, 121, and 585 peripheral blood gene transcripts, respectively. Thirty-one transcript changes were shared between the 1- and 8-week time points (seven upregulated, 24 downregulated). Differences were detected between the escitalopram- and bupropion-treated subjects, although there was no significant association between GE changes and clinical outcome. A subset of 18 genes overlapped with those previously identified as differentially expressed in subjects with MDD compared with healthy control subjects. There was statistically significant overlap between genes differentially expressed in the current and previous studies, with 10 genes overlapping in at least two previous studies. There was no enrichment for genes overexpressed in nervous system cell types, but there was a trend toward enrichment for genes in the WNT/β-catenin pathway in the anterior thalamus; three genes in this pathway showed differential expression in the present and in three previous studies. Our dataset and other similar studies will provide an important source of information about potential biomarkers of recovery and for potential dysregulation of GE in MDD.
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Affiliation(s)
- Ian A Cook
- Neuromodulation Division, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Bioengineering, Henry Samueli School of Engineering at Applied Science, University of California, Los Angeles, Los Angeles, CA, United States
| | - Eliza Congdon
- Neuromodulation Division, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - David E Krantz
- Neuromodulation Division, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Aimee M Hunter
- Neuromodulation Division, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Giovanni Coppola
- Neuromodulation Division, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Steven P Hamilton
- Department of Psychiatry, Kaiser Permanente Northern California, San Francisco, CA, United States.,Department of Psychiatry, University of California, San Francisco, San Francisco, CA, United States
| | - Andrew F Leuchter
- Neuromodulation Division, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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Li W, Xu L. Epigenetic Function of TET Family, 5-Methylcytosine, and 5-Hydroxymethylcytosine in Hematologic Malignancies. Oncol Res Treat 2019; 42:309-318. [PMID: 31055566 DOI: 10.1159/000498947] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 02/14/2019] [Indexed: 11/19/2022]
Abstract
DNA methylation plays significant roles in a variety of biological and pathological processes including mammalian development, genomic imprinting, retrotransposon silencing, and X-chromosome inactivation. Recent discoveries indicated that ten-eleven translocation (TET) family of dioxygenases can convert 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC). The TET family includes three members: TET1, TET2, and TET3. With increasing evidence, more and more biological and pathological processes in which 5-hmC and TET family serve unparalleled biological roles are noticed, for example, DNA demethylation and transcriptional regulation of different target genes, which are involved in many human diseases, especially hematologic malignancies, resembling chronic myelomonocytic leukemia, myelodysplastic syndromes, and so on. In this review, we focus on the diverse functions of TET family and the novel epigenetic marks, 5-mC and 5-hmC, in hematologic malignancies. This review will provide valuable insights into the potential targets of hematologic malignancies. Further understanding of the normal and pathological functions of TET family may provide new methods to develop novel epigenetic therapies for treating hematologic malignancies.
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Affiliation(s)
- Wei Li
- Department of Immunotherapy, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Linping Xu
- Department of Research and Foreign Affairs, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China,
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37
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Bitar M, Barry G. Multiple Innovations in Genetic and Epigenetic Mechanisms Cooperate to Underpin Human Brain Evolution. Mol Biol Evol 2019; 35:263-268. [PMID: 29177456 DOI: 10.1093/molbev/msx303] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Our knowledge of how the human brain differs from those of other species in terms of evolutionary adaptations and functionality is limited. Comparative genomics reveal valuable insight, especially the expansion of human-specific noncoding regulatory and repeat-containing regions. Recent studies add to our knowledge of evolving brain function by investigating cellular mechanisms such as protein emergence, extensive sequence editing, retrotransposon activity, dynamic epigenetic modifications, and multiple noncoding RNA functions. These findings present an opportunity to combine newly discovered genetic and epigenetic mechanisms with more established concepts into a more comprehensive picture to better understand the uniquely evolved human brain.
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Affiliation(s)
- Mainá Bitar
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Guy Barry
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
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38
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Rustad SR, Papale LA, Alisch RS. DNA Methylation and Hydroxymethylation and Behavior. Curr Top Behav Neurosci 2019; 42:51-82. [PMID: 31392630 DOI: 10.1007/7854_2019_104] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Environmentally sensitive molecular mechanisms in the brain, such as DNA methylation, have become a significant focus of neuroscience research because of mounting evidence indicating that they are critical in response to social situations, stress, threats, and behavior. The recent identification of 5-hydroxymethylcytosine (5hmC), which is enriched in the brain (tenfold over peripheral tissues), raises new questions as to the role of this base in mediating epigenetic effects in the brain. The development of genome-wide methods capable of distinguishing 5-methylcytosine (5mC) from 5hmC has revealed that a growing number of behaviors are linked to independent disruptions of 5mC and 5hmC levels, further emphasizing the unique importance of both of these modifications in the brain. Here, we review the recent links that indicate DNA methylation (both 5mC and 5hmC) is highly dynamic and that perturbations in this modification may contribute to behaviors related to psychiatric disorders and hold clinical relevance.
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Affiliation(s)
| | - Ligia A Papale
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | - Reid S Alisch
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA. .,Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
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39
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Zhao S, Jia T, Tang Y, Zhang X, Mao H, Tian X, Li R, Ma L, Chen G. Reduced mRNA and Protein Expression Levels of Tet Methylcytosine Dioxygenase 3 in Endothelial Progenitor Cells of Patients of Type 2 Diabetes With Peripheral Artery Disease. Front Immunol 2018; 9:2859. [PMID: 30574144 PMCID: PMC6291445 DOI: 10.3389/fimmu.2018.02859] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 11/20/2018] [Indexed: 02/05/2023] Open
Abstract
Endothelial progenitor cells (EPCs) with immunological properties repair microvasculature to prevent the complications in patients with diabetes. Epigenetic changes such as DNA methylation alter the functions of cells. Tet methylcytosine dioxygenases (TETs) are enzymes responsible for the demethylation of cytosine on genomic DNA in cells. We hypothesized that EPCs of diabetic patients with peripheral artery disease (D-PAD) might have altered expression levels of TETs. Subjects who were non-diabetic (ND, n = 22), with diabetes only (D, n = 29) and with D-PAD (n = 22) were recruited for the collection of EPCs, which were isolated and subjected to analysis. The mRNA and protein expression levels of TET1, TET2, and TET3 were determined using real-time PCR and immunoblot, respectively. The TET1 mRNA expression level in ND group was lower than that in the D and D-PAD groups. The TET3 mRNA level in the ND group was higher than that in the D group, which was higher than that in the D-PAD group. The TET1 protein level in the D-PAD group, but not the D group, was higher than that in the ND group. The TET2 protein level in the D-PAD group, but not the D group, was lower than that in the ND group. The TET3 protein level in the ND group was higher than that in the D group, which was higher than that in the D-PAD group, which is the lowest among the three groups. The changes of TETs protein levels were due to the alterations of their transcripts. These probably lead to epigenetic changes, which may be responsible for the reductions of EPCs numbers and functions in patients with the D-PAD. The expression pattern of TET3 mRNA and TET3 protein in EPCs may be a biomarker of angiopathy in diabetic patients.
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Affiliation(s)
- Shi Zhao
- Department of Endocrinology, Wuhan Central Hospital, Wuhan, China
| | - Ting Jia
- Department of Endocrinology, Wuhan Central Hospital, Wuhan, China
| | - Yang Tang
- School of Social Sciences, Nanyang Technology University, Singapore, Singapore
| | | | - Hong Mao
- Department of Endocrinology, Wuhan Central Hospital, Wuhan, China
| | - Xiaojia Tian
- School of Social Sciences, Nanyang Technology University, Singapore, Singapore
| | - Rui Li
- School of Social Sciences, Nanyang Technology University, Singapore, Singapore
| | - Lu Ma
- School of Social Sciences, Nanyang Technology University, Singapore, Singapore
| | - Guoxun Chen
- Department of Nutrition, University of Tennessee, Knoxville, TN, United States
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40
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Auta J, Gatta E, Davis JM, Pandey SC, Guidotti A. Potential role for histone deacetylation in chronic diazepam-induced downregulation of α1-GABA A receptor subunit expression. Pharmacol Res Perspect 2018; 6:e00416. [PMID: 29951207 PMCID: PMC6019704 DOI: 10.1002/prp2.416] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 05/15/2018] [Indexed: 01/13/2023] Open
Abstract
Corroborating evidence indicate that the downregulation of GABAA receptor subunit expression may underlie tolerance to the anticonvulsant and anxiolytic actions of benzodiazepine (BZ) ligands that act as full allosteric modulators (FAMs) of GABA actions at a variety of GABAA receptor subtypes. We and others have shown that 10-14 days treatment with increasing doses of diazepam (a FAM) resulted in anticonvulsant tolerance and decreased the expression of the α1 GABAA receptor subunit mRNA and protein in frontal cortex. In addition, we have also shown that long-term treatment with imidazenil, a partial allosteric modulator of GABA action at selective GABAA receptor subtypes, fail to change the expression of the α1 subunit mRNA or induce tolerance to its anticonvulsant or anxiolytic action. However, little is known regarding the potential role of epigenetic mechanisms on long-term BZ-induced downregulation of GABAA receptor subunit. Therefore, we examined the role of histone acetylation and DNA methylation mechanisms on long-term diazepam-induced downregulation of the α1 subunit mRNA expression in rat frontal cortex. We found that 10 days treatment with increasing doses of diazepam but not imidazenil decreased the expression of the α1 GABAA receptor subunit mRNA and promoter acetylation in frontal cortex. In addition, we also found that 10 days treatment with diazepam but not imidazenil increased the expression of histone deacetylase (HDAC) 1 and 2 in frontal cortex. Thus, the increased expression of HDAC1 and HDAC2 (class 1 HDACs) and consequently increased histone deacetylation mechanism of this class 1 HDACs, may underlie long-term diazepam-induced decreased expression of the α1 GABAA receptor subunit mRNA in frontal cortex.
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Affiliation(s)
- James Auta
- Center for Alcohol Research in EpigeneticsDepartment of PsychiatryCollege of MedicineUniversity of IllinoisChicagoIllinois
- The Psychiatric InstituteDepartment of PsychiatryCollege of MedicineUniversity of IllinoisChicagoIllinois
| | - Eleonora Gatta
- Center for Alcohol Research in EpigeneticsDepartment of PsychiatryCollege of MedicineUniversity of IllinoisChicagoIllinois
- The Psychiatric InstituteDepartment of PsychiatryCollege of MedicineUniversity of IllinoisChicagoIllinois
| | - John M. Davis
- The Psychiatric InstituteDepartment of PsychiatryCollege of MedicineUniversity of IllinoisChicagoIllinois
| | - Subhash C. Pandey
- Center for Alcohol Research in EpigeneticsDepartment of PsychiatryCollege of MedicineUniversity of IllinoisChicagoIllinois
- Jesse Brown VA Medical CenterChicagoIllinois
| | - Alessandro Guidotti
- Center for Alcohol Research in EpigeneticsDepartment of PsychiatryCollege of MedicineUniversity of IllinoisChicagoIllinois
- The Psychiatric InstituteDepartment of PsychiatryCollege of MedicineUniversity of IllinoisChicagoIllinois
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41
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Peedicayil J, Kumar A. Epigenetic Drugs for Mood Disorders. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2018; 157:151-174. [PMID: 29933949 DOI: 10.1016/bs.pmbts.2018.01.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
There is increasing evidence that changes in epigenetic mechanisms of gene expression are involved in the pathogenesis of mood disorders. Such evidence stems from studies conducted on postmortem brain tissues and peripheral cells or tissues of patients with mood disorders. This article describes and discusses the epigenetic changes in the mood disorders (major depressive disorder and bipolar disorder) found to date. The article also describes and discusses preclinical drug trials of epigenetic drugs for treating mood disorders. In addition, nonrandomized and randomized controlled trials of nutritional drugs with effects on epigenetic mechanisms of gene expression in patients with major depressive disorder and bipolar disorder are discussed. Trials of epigenetic drugs and nutritional drugs with epigenetic effects are showing promising results for the treatment of mood disorders. Thus, epigenetic drugs and nutritional drugs with epigenetic effects could be useful in the treatment of patients with these disorders.
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42
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Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families. Mol Psychiatry 2018; 23:973-984. [PMID: 28397838 DOI: 10.1038/mp.2017.60] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 02/06/2017] [Accepted: 02/10/2017] [Indexed: 12/14/2022]
Abstract
Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7 and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.
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43
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Grayson DR, Guidotti A. DNA Methylation in Animal Models of Psychosis. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2018; 157:105-132. [PMID: 29933947 DOI: 10.1016/bs.pmbts.2017.12.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Schizophrenia (SZ) is a debilitating disease that impacts 1% of the population worldwide. Association studies have shown that inherited genetic mutations account for a portion of disease risk. However, environmental factors play an important role in the pathophysiology of the disease by altering cellular epigenetic marks at the level of chromatin. Postmortem brain studies of SZ subjects suggest that the dynamic equilibrium between DNA methylation and demethylation network components is disrupted at the level of individual SZ target genes. Herein, we review the role of DNA methylation and demethylation in the context of what is currently known regarding SZ. Furthermore, we describe the deficits that accompany two mouse models of SZ. The chronic methionine mouse model of SZ is predicated on the administration of methionine to SZ patients and controls in the context of clinical studies that were carried out during the 1960s and 1970s. The prenatal restraint stress model of SZ is based on a prolonged stress paradigm administered to pregnant dams during gestation days 7-21. The adult offspring of these dams show various behavioral and biochemical deficits in adulthood. Both models are epigenetic in origin and mimic the positive and negative symptoms, as well as the cognitive endophenotypes commonly observed in SZ patients. We also discuss the utility of typical and atypical antipsychotic drugs in alleviating these symptoms in each model.
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Affiliation(s)
- Dennis R Grayson
- Center for Alcohol Research in Epigenetics, University of Illinois, Chicago, IL, United States.
| | - Alessandro Guidotti
- Center for Alcohol Research in Epigenetics, University of Illinois, Chicago, IL, United States
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44
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Understanding the molecular mechanisms underlying mood stabilizer treatments in bipolar disorder: Potential involvement of epigenetics. Neurosci Lett 2018; 669:24-31. [DOI: 10.1016/j.neulet.2016.06.045] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 06/21/2016] [Accepted: 06/22/2016] [Indexed: 11/23/2022]
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45
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Ovenden ES, McGregor NW, Emsley RA, Warnich L. DNA methylation and antipsychotic treatment mechanisms in schizophrenia: Progress and future directions. Prog Neuropsychopharmacol Biol Psychiatry 2018; 81:38-49. [PMID: 29017764 DOI: 10.1016/j.pnpbp.2017.10.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 10/01/2017] [Accepted: 10/04/2017] [Indexed: 12/15/2022]
Abstract
Antipsychotic response in schizophrenia is a complex, multifactorial trait influenced by pharmacogenetic factors. With genetic studies thus far providing little biological insight or clinical utility, the field of pharmacoepigenomics has emerged to tackle the so-called "missing heritability" of drug response in disease. Research on psychiatric disorders has only recently started to assess the link between epigenetic alterations and treatment outcomes. DNA methylation, the best characterised epigenetic mechanism to date, is discussed here in the context of schizophrenia and antipsychotic treatment outcomes. The majority of published studies have assessed the influence of antipsychotics on methylation levels in specific neurotransmitter-associated candidate genes or at the genome-wide level. While these studies illustrate the epigenetic modifications associated with antipsychotics, very few have assessed clinical outcomes and the potential of differential DNA methylation profiles as predictors of antipsychotic response. Results from other psychiatric disorder studies, such as depression and bipolar disorder, provide insight into what may be achieved by schizophrenia pharmacoepigenomics. Other aspects that should be addressed in future research include methodological challenges, such as tissue specificity, and the influence of genetic variation on differential methylation patterns.
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Affiliation(s)
- Ellen S Ovenden
- Department of Genetics, Stellenbosch University, Stellenbosch 7600, South Africa
| | - Nathaniel W McGregor
- Department of Genetics, Stellenbosch University, Stellenbosch 7600, South Africa
| | - Robin A Emsley
- Department of Psychiatry, Stellenbosch University, Tygerberg 7505, South Africa
| | - Louise Warnich
- Department of Genetics, Stellenbosch University, Stellenbosch 7600, South Africa.
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46
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Boschen KE, Keller SM, Roth TL, Klintsova AY. Epigenetic mechanisms in alcohol- and adversity-induced developmental origins of neurobehavioral functioning. Neurotoxicol Teratol 2018; 66:63-79. [PMID: 29305195 DOI: 10.1016/j.ntt.2017.12.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 12/11/2017] [Accepted: 12/26/2017] [Indexed: 12/13/2022]
Abstract
The long-term effects of developmental alcohol and stress exposure are well documented in both humans and non-human animal models. Damage to the brain and attendant life-long impairments in cognition and increased risk for psychiatric disorders are debilitating consequences of developmental exposure to alcohol and/or psychological stress. Here we discuss evidence for a role of epigenetic mechanisms in mediating these consequences. While we highlight some of the common ways in which stress or alcohol impact the epigenome, we point out that little is understood of the epigenome's response to experiencing both stress and alcohol exposure, though stress is a contributing factor as to why women drink during pregnancy. Advancing our understanding of this relationship is of critical concern not just for the health and well-being of individuals directly exposed to these teratogens, but for generations to come.
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Affiliation(s)
- K E Boschen
- Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC 27599, United States
| | - S M Keller
- Department of Psychological and Brain Sciences, University of Delaware, Newark, DE 19716, United States
| | - T L Roth
- Department of Psychological and Brain Sciences, University of Delaware, Newark, DE 19716, United States.
| | - A Y Klintsova
- Department of Psychological and Brain Sciences, University of Delaware, Newark, DE 19716, United States.
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47
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Kader F, Ghai M, Maharaj L. The effects of DNA methylation on human psychology. Behav Brain Res 2017; 346:47-65. [PMID: 29237550 DOI: 10.1016/j.bbr.2017.12.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 11/01/2017] [Accepted: 12/05/2017] [Indexed: 01/05/2023]
Abstract
DNA methylation is a fundamental epigenetic modification in the human genome; pivotal in development, genomic imprinting, X inactivation, chromosome stability, gene expression and methylation aberrations are involved in an array of human diseases. Methylation at promoters is associated with transcriptional repression, whereas gene body methylation is generally associated with gene expression. Extrinsic factors such as age, diets and lifestyle affect DNA methylation which consequently alters gene expression. Stress, anxiety, depression, life satisfaction, emotion among numerous other psychological factors also modify DNA methylation patterns. This correlation is frequently investigated in four candidate genes; NR3C1, SLC6A4, BDNF and OXTR, since regulation of these genes directly impact responses to social situations, stress, threats, behaviour and neural functions. Such studies underpin the hypothesis that DNA methylation is involved in deviant human behaviour, psychological and psychiatric conditions. These candidate genes may be targeted in future to assess the correlation between methylation, social experiences and long-term behavioural phenotypes in humans; and may potentially serve as biomarkers for therapeutic intervention.
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Affiliation(s)
- Farzeen Kader
- School of Life Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4000 South Africa.
| | - Meenu Ghai
- School of Life Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4000 South Africa.
| | - Leah Maharaj
- School of Life Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4000 South Africa.
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48
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Variation in global DNA hydroxymethylation with age associated with schizophrenia. Psychiatry Res 2017; 257:497-500. [PMID: 28841512 DOI: 10.1016/j.psychres.2017.08.022] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 08/08/2017] [Accepted: 08/12/2017] [Indexed: 12/31/2022]
Abstract
To improve understanding of DNA hydroxymethylation (5hmC) and methylation (5mC) in the development of schizophrenia, this study examined global 5hmC and 5mC levels in peripheral blood DNA of 264 patients with schizophrenia and 221 controls and observed increased 5mC levels in the patients and increased 5hmC levels in male patients but decreased levels in female patients as compared with the controls. The 5mC level displayed a gender-dependent positive correlation with age and the 5hmC level displayed a correlation with age positively in controls but negatively in patients, and their role in the pathogenesis of schizophrenia remains to be elucidated.
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49
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Spiers H, Hannon E, Schalkwyk LC, Bray NJ, Mill J. 5-hydroxymethylcytosine is highly dynamic across human fetal brain development. BMC Genomics 2017; 18:738. [PMID: 28923016 PMCID: PMC5604137 DOI: 10.1186/s12864-017-4091-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 08/25/2017] [Indexed: 12/30/2022] Open
Abstract
Background Epigenetic processes play a key role in orchestrating transcriptional regulation during the development of the human central nervous system. We previously described dynamic changes in DNA methylation (5mC) occurring during human fetal brain development, but other epigenetic processes operating during this period have not been extensively explored. Of particular interest is DNA hydroxymethylation (5hmC), a modification that is enriched in the human brain and hypothesized to play an important role in neuronal function, learning and memory. In this study, we quantify 5hmC across the genome of 71 human fetal brain samples spanning 23 to 184 days post-conception. Results We identify widespread changes in 5hmC occurring during human brain development, notable sex-differences in 5hmC in the fetal brain, and interactions between 5mC and 5hmC at specific sites. Finally, we identify loci where 5hmC in the fetal brain is associated with genetic variation. Conclusions This study represents the first systematic analysis of dynamic changes in 5hmC across human neurodevelopment and highlights the potential importance of this modification in the human brain. A searchable database of our fetal brain 5hmC data is available as a resource to the research community at http://www.epigenomicslab.com/online-data-resources. Electronic supplementary material The online version of this article doi:(10.1186/s12864-017-4091-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Helen Spiers
- Department of Physics, University of Oxford, Oxford, OX1 3RH, UK
| | - Eilis Hannon
- University of Exeter Medical School, RILD Building, Royal Devon and Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK
| | | | - Nicholas J Bray
- MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, CF24 4HQ, UK
| | - Jonathan Mill
- University of Exeter Medical School, RILD Building, Royal Devon and Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
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Kwon W, Kim HS, Jeong J, Sung Y, Choi M, Park S, Lee J, Jang S, Kim SH, Lee S, Kim MO, Ryoo ZY. Tet1 overexpression leads to anxiety-like behavior and enhanced fear memories via the activation of calcium-dependent cascade through Egr1 expression in mice. FASEB J 2017; 32:390-403. [PMID: 28899881 DOI: 10.1096/fj.201601340rr] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 09/05/2017] [Indexed: 11/11/2022]
Abstract
Ten-eleven translocation methylcytosine dioxygenase 1 (Tet1) initiates DNA demethylation by converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) at CpG-rich regions of genes, which have key roles in adult neurogenesis and memory. In addition, the overexpression of Tet1 with 5-hmC alteration in patients with psychosis has also been reported, for instance in schizophrenia and bipolar disorders. The mechanism underlying Tet1 overexpression in the brain; however, is still elusive. In the present study, we found that Tet1-transgenic (Tet1-TG) mice displayed abnormal behaviors involving elevated anxiety and enhanced fear memories. We confirmed that Tet1 overexpression affected adult neurogenesis with oligodendrocyte differentiation in the hippocampal dentate gyrus of Tet1-TG mice. In addition, Tet1 overexpression induced the elevated expression of immediate early genes, such as Egr1, c-fos, Arc, and Bdnf, followed by the activation of intracellular calcium signals (i.e., CamKII, ERK, and CREB) in prefrontal and hippocampal neurons. The expression of GABA receptor subunits (Gabra2 and Gabra4) fluctuated in the prefrontal cortex and hippocampus. We evaluated the effects of Tet1 overexpression on intracellular calcium-dependent cascades by activating the Egr1 promoter in vitro Tet1 enhanced Egr1 expression, which may have led to alterations in Gabra2 and Gabra4 expression in neurons. Taken together, we suggest that the Tet1 overexpression in our Tet1-TG mice can be applied as an effective model for studying various stress-related diseases that show hyperactivation of intracellular calcium-dependent cascades in the brain.-Kwon, W., Kim, H.-S., Jeong, J., Sung, Y., Choi, M., Park, S., Lee, J., Jang, S., Kim, S. H., Lee, S., Kim, M. O., Ryoo, Z. Y. Tet1 overexpression leads to anxiety-like behavior and enhanced fear memories via the activation of calcium-dependent cascade through Egr1 expression in mice.
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Affiliation(s)
- Wookbong Kwon
- School of Life Science, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea
| | - Hyeng-Soo Kim
- School of Life Science, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea.,Institute of Life Science and Biotechnology, Kyungpook National University, Daegu, South Korea; and
| | - Jain Jeong
- School of Life Science, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea
| | - Yonghun Sung
- School of Life Science, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea
| | - Minjee Choi
- School of Life Science, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea
| | - Song Park
- School of Life Science, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea
| | - Jinhee Lee
- School of Life Science, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea
| | - Soyoung Jang
- School of Life Science, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea
| | - Sung Hyun Kim
- Institute of Life Science and Biotechnology, Kyungpook National University, Daegu, South Korea; and
| | - Sanggyu Lee
- School of Life Science, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea
| | - Myoung Ok Kim
- The School of Animal Biotechnology (BT) Science, Kyungpook National University, Sangju, South Korea
| | - Zae Young Ryoo
- School of Life Science, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea;
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