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Skeletal muscle DNA methylation modifications and psychopharmacologic treatment in bipolar disorder.European Neuropsychopharmacology : the... Dec 2019Both severe mental illness and atypical antipsychotics have been independently associated with insulin resistance and weight gain. Altered regulation of skeletal muscle...
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.
Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Cross-Sectional Studies; DNA Methylation; Female; Humans; Male; Middle Aged; Muscle, Skeletal; Treatment Outcome
PubMed: 31635791
DOI: 10.1016/j.euroneuro.2019.10.001 -
Nucleic Acids Research Jul 2022We analysed DNA methylation data from 30 datasets comprising 3474 individuals, 19 tissues and 8 ethnicities at CpGs covered by the Illumina450K array. We identified 4143...
We analysed DNA methylation data from 30 datasets comprising 3474 individuals, 19 tissues and 8 ethnicities at CpGs covered by the Illumina450K array. We identified 4143 hypervariable CpGs ('hvCpGs') with methylation in the top 5% most variable sites across multiple tissues and ethnicities. hvCpG methylation was influenced but not determined by genetic variation, and was not linked to probe reliability, epigenetic drift, age, sex or cell heterogeneity effects. hvCpG methylation tended to covary across tissues derived from different germ-layers and hvCpGs were enriched for proximity to ERV1 and ERVK retrovirus elements. hvCpGs were also enriched for loci previously associated with periconceptional environment, parent-of-origin-specific methylation, and distinctive methylation signatures in monozygotic twins. Together, these properties position hvCpGs as strong candidates for studying how stochastic and/or environmentally influenced DNA methylation states which are established in the early embryo and maintained stably thereafter can influence life-long health and disease.
Topics: Humans; DNA Methylation; Reproducibility of Results; Embryo, Mammalian; CpG Islands; Ethnicity
PubMed: 35713545
DOI: 10.1093/nar/gkac503 -
Neuroscience and Biobehavioral Reviews May 2020DNA methylation (DNAm) - an epigenetic process that regulates gene expression - may represent a mechanism for the biological embedding of early traumatic experiences,...
DNA methylation (DNAm) - an epigenetic process that regulates gene expression - may represent a mechanism for the biological embedding of early traumatic experiences, including childhood maltreatment. Here, we conducted the first systematic review of human studies linking childhood maltreatment to DNAm. In total, 72 studies were included in the review (2008-2018). The majority of extant studies (i) were based on retrospective data in adults, (ii) employed a candidate gene approach (iii) focused on global maltreatment, (iv) were based on easily accessible peripheral tissues, typically blood; and (v) were cross-sectional. Two-thirds of studies (n = 48) also examined maltreatment-related outcomes, such as stress reactivity and psychiatric symptoms. While findings generally support an association between childhood maltreatment and altered patterns of DNAm, factors such as the lack of longitudinal data, low comparability across studies as well as potential genetic and 'pre-exposure' environmental confounding currently limit the conclusions that can be drawn. Key challenges are discussed and concrete recommendations for future research are provided to move the field forward.
Topics: Adult Survivors of Child Abuse; Adverse Childhood Experiences; DNA Methylation; Epigenesis, Genetic; Humans; Mental Disorders
PubMed: 32081689
DOI: 10.1016/j.neubiorev.2020.02.019 -
Ageing Research Reviews Aug 2018The multi-tissue DNA methylation estimator of chronological age (DNAm-age) has been associated with a wide range of exposures and health outcomes. Still, it is unclear... (Review)
Review
The multi-tissue DNA methylation estimator of chronological age (DNAm-age) has been associated with a wide range of exposures and health outcomes. Still, it is unclear how DNAm-age can have such broad relationships and how it can be best utilized as a biomarker. Understanding DNAm-age's molecular relationships is a promising approach to address this critical knowledge gap. In this review, we discuss the existing literature regarding DNAm-age's molecular relationships in six major categories: animal model systems, cancer processes, cellular aging processes, immune system processes, metabolic processes, and nucleic acid processes. We also present perspectives regarding the future of DNAm-age research, including the need to translate a greater number of ongoing research efforts to experimental and animal model systems.
Topics: Animals; Biomarkers; Cellular Senescence; DNA Methylation; Humans; Immunity, Cellular; Neoplasms
PubMed: 29698722
DOI: 10.1016/j.arr.2018.04.005 -
Clinical Epigenetics Oct 2021Histone modification is an important form of epigenetic regulation. Thereinto, histone methylation is a critical determination of chromatin states, participating in... (Review)
Review
Histone modification is an important form of epigenetic regulation. Thereinto, histone methylation is a critical determination of chromatin states, participating in multiple cellular processes. As a conserved histone methylation mark, histone 3 lysine 36 trimethylation (H3K36me3) can mediate multiple transcriptional-related events, such as the regulation of transcriptional activity, transcription elongation, pre-mRNA alternative splicing, and RNA mA methylation. Additionally, H3K36me3 also contributes to DNA damage repair. Given the crucial function of H3K36me3 in genome regulation, the roles of H3K36me3 and its sole methyltransferase SETD2 in pathogenesis, especially malignancies, have been emphasized in many studies, and it is conceivable that disruption of histone methylation regulatory network composed of "writer", "eraser", "reader", and the mutation of H3K36me3 codes have the capacity of powerfully modulating cancer initiation and development. Here we review H3K36me3-mediated biological processes and summarize the latest findings regarding its role in cancers. We highlight the significance of epigenetic combination therapies in cancers.
Topics: DNA Methylation; Epigenesis, Genetic; Histones; Humans; Neoplasms
PubMed: 34715919
DOI: 10.1186/s13148-021-01187-2 -
Integrative and Comparative Biology Jul 2014An organism's ability to adapt to its environment depends on its ability to regulate and maintain tissue specific, temporal patterns of gene transcription in response to... (Review)
Review
An organism's ability to adapt to its environment depends on its ability to regulate and maintain tissue specific, temporal patterns of gene transcription in response to specific environmental cues. Epigenetic mechanisms are responsible for many of the intricacies of a gene's regulation that alter expression patterns without affecting the genetic sequence. In particular, DNA methylation has been shown to have an important role in regulating early development and in some human diseases. Within these domains, DNA methylation has been extensively characterized over the past 60 years, but the discovery of its role in regulating behavioral outcomes has led to renewed interest in its potential roles in animal behavior and phenotypic plasticity. The conservation of DNA methylation across the animal kingdom suggests a possible role in the plasticity of genomic responses to environmental cues in natural environments. Here, we review the historical context for the study of DNA methylation, its function and mechanisms, and provide examples of gene/environment interactions in response to social and seasonal cues. Finally, we discuss useful tools to interrogate and dissect the function of DNA methylation in non-model organisms.
Topics: DNA Methylation; Environment; Epigenesis, Genetic; Gene Expression Regulation; Humans; Models, Biological; Seasons; Social Environment
PubMed: 24813708
DOI: 10.1093/icb/icu034 -
Clinical Epigenetics May 2024DNA methylation influences gene expression and function in the pathophysiology of type 2 diabetes mellitus (T2DM). Mapping of T2DM-associated DNA methylation could aid...
OBJECTIVE
DNA methylation influences gene expression and function in the pathophysiology of type 2 diabetes mellitus (T2DM). Mapping of T2DM-associated DNA methylation could aid early detection and/or therapeutic treatment options for diabetics.
DESIGN
A systematic literature search for associations between T2DM and DNA methylation was performed. Prospero registration ID: CRD42020140436.
METHODS
PubMed and ScienceDirect databases were searched (till October 19, 2023). Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and New Castle Ottawa scale were used for reporting the selection and quality of the studies, respectively.
RESULT
Thirty-two articles were selected. Four of 130 differentially methylated genes in blood, adipose, liver or pancreatic islets (TXNIP, ABCG1, PPARGC1A, PTPRN2) were reported in > 1 study. TXNIP was hypomethylated in diabetic blood across ethnicities. Gene enrichment analysis of the differentially methylated genes highlighted relevant disease pathways (T2DM, type 1 diabetes and adipocytokine signaling). Three prospective studies reported association of methylation in IGFBP2, MSI2, FTO, TXNIP, SREBF1, PHOSPHO1, SOCS3 and ABCG1 in blood at baseline with incident T2DM/hyperglycemia. Sex-specific differential methylation was reported only for HOOK2 in visceral adipose tissue (female diabetics: hypermethylated, male diabetics: hypomethylated). Gene expression was inversely associated with methylation status in 8 studies, in genes including ABCG1 (blood), S100A4 (adipose tissue), PER2 (pancreatic islets), PDGFA (liver) and PPARGC1A (skeletal muscle).
CONCLUSION
This review summarizes available evidence for using DNA methylation patterns to unravel T2DM pathophysiology. Further validation studies in diverse populations will set the stage for utilizing this knowledge for identifying early diagnostic markers and novel druggable pathways.
Topics: Female; Humans; Male; Carrier Proteins; Diabetes Mellitus, Type 2; DNA Methylation; Epigenesis, Genetic
PubMed: 38755631
DOI: 10.1186/s13148-024-01670-6 -
International Journal of Molecular... Mar 2021DNA methylation is a prevalent regulatory modification in prokaryotes and eukaryotes. -methyladenine (mA) and -methyladenine (mA) have been found to be capable of...
DNA methylation is a prevalent regulatory modification in prokaryotes and eukaryotes. -methyladenine (mA) and -methyladenine (mA) have been found to be capable of altering DNA structures via disturbing Watson-Crick base pairing. However, little has been known about their influences on non-B DNA structures, which are associated with genetic instabilities. In this work, we investigated the effects of mA and mA on both the structure and thermodynamic stability of a newly reported DNA minidumbbell formed by two TTTA tetranucleotide repeats. As revealed by the results of nuclear magnetic resonance spectroscopic studies, both mA and mA favored the formation of a T·mA and T·mA Hoogsteen base pair, respectively. More intriguingly, the mA and mA modifications brought about stabilization and destabilization effects on the DNA minidumbbell, respectively. This work provides new biophysical insights into the effects of adenine methylation on the structure and thermodynamic stability of DNA.
Topics: Adenine; Base Pairing; DNA; DNA Methylation; Hydrogen Bonding; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Nucleic Acid Conformation; Nucleotide Motifs; Thermodynamics
PubMed: 33807305
DOI: 10.3390/ijms22073633 -
Plant Physiology Aug 2015DNA methylation within transcribed genes is commonly found in diverse animals and plants. Here, we provide an overview of recent advances and the remaining mystery... (Review)
Review
DNA methylation within transcribed genes is commonly found in diverse animals and plants. Here, we provide an overview of recent advances and the remaining mystery regarding intragenic DNA methylation.
Topics: DNA Methylation; DNA, Intergenic; DNA, Plant; Plants
PubMed: 26143255
DOI: 10.1104/pp.15.00543 -
Nature Genetics Dec 2022Cytosine methylation efficiently silences CpG-rich regulatory regions of genes and repeats in mammalian genomes. To what extent this entails direct inhibition of...
Cytosine methylation efficiently silences CpG-rich regulatory regions of genes and repeats in mammalian genomes. To what extent this entails direct inhibition of transcription factor (TF) binding versus indirect inhibition via recruitment of methyl-CpG-binding domain (MBD) proteins is unclear. Here we show that combinatorial genetic deletions of all four proteins with functional MBDs in mouse embryonic stem cells, derived neurons or a human cell line do not reactivate genes or repeats with methylated promoters. These do, however, become activated by methylation-restricted TFs if DNA methylation is removed. We identify several causal TFs in neurons, including ONECUT1, which is methylation sensitive only at a motif variant. Rampantly upregulated retrotransposons in methylation-free neurons feature a CRE motif, which activates them in the absence of DNA methylation via methylation-sensitive binding of CREB1. Our study reveals methylation-sensitive TFs in vivo and argues that direct inhibition, rather than indirect repression by the tested MBD proteins, is the prevailing mechanism of methylation-mediated repression at regulatory regions and repeats.
Topics: Animals; Humans; Mice; DNA Methylation; Hepatocyte Nuclear Factor 6; Mammals; Transcription Factors
PubMed: 36471082
DOI: 10.1038/s41588-022-01241-6