The methylome of the human frontal cortex across development

DNA methylation (DNAm) plays an important role in epigenetic regulation of gene expression, orchestrating tissue differentiation and development during all stages of mammalian life. This epigenetic control is especially important in the human brain, with extremely dynamic gene expression during fetal and infant life, and becomes progressively more stable at later periods of development . We characterized the epigenetic state of the developing and aging human frontal cortex in post-mortem tissue from 351 individuals across the lifespan using the Illumina 450k DNA methylation microarray. The largest changes in the methylome occur at birth at varying spatial resolutions - we identify 359,087 differentially methylated loci, which form 23,732 significant differentially methylated regions (DMRs). There were also 298 regions of long-range changes in DNAm, termed "blocks", associated with birth that strongly overlap previously published colon cancer blocks. We then identify 55,439 DMRs associated with development and aging, of which 61.9% significantly associate with nearby gene expression levels. Lastly, we find enrichment of genomic loci of risk for schizophrenia and several other common diseases among these developmental DMRs. These data, integrated with existing genetic and transcriptomic data, create a rich genomic resource across brain development.

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Faculty Opinions recommendation of Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725971928.793539804 ◽

2017 ◽

Author(s):

Christopher Gregg

Keyword(s):

Dna Methylation ◽

Frontal Cortex ◽

Human Frontal Cortex

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A Sparse and Low-Rank Regression Model for Identifying the Relationships Between DNA Methylation and Gene Expression Levels in Gastric Cancer and the Prediction of Prognosis

Genes ◽

10.3390/genes12060854 ◽

2021 ◽

Vol 12 (6) ◽

pp. 854

Author(s):

Yishu Wang ◽

Lingyun Xu ◽

Dongmei Ai

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Dna Methylation ◽

Regression Model ◽

The Cancer Genome Atlas ◽

Low Rank ◽

Expression Levels ◽

Rank Regression ◽

Prediction Of Prognosis ◽

Gene Expression Levels

DNA methylation is an important regulator of gene expression that can influence tumor heterogeneity and shows weak and varying expression levels among different genes. Gastric cancer (GC) is a highly heterogeneous cancer of the digestive system with a high mortality rate worldwide. The heterogeneous subtypes of GC lead to different prognoses. In this study, we explored the relationships between DNA methylation and gene expression levels by introducing a sparse low-rank regression model based on a GC dataset with 375 tumor samples and 32 normal samples from The Cancer Genome Atlas database. Differences in the DNA methylation levels and sites were found to be associated with differences in the expressed genes related to GC development. Overall, 29 methylation-driven genes were found to be related to the GC subtypes, and in the prognostic model, we explored five prognoses related to the methylation sites. Finally, based on a low-rank matrix, seven subgroups were identified with different methylation statuses. These specific classifications based on DNA methylation levels may help to account for heterogeneity and aid in personalized treatments.

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DNA methylation and regulation of gene expression: Guardian of our health

The Nucleus ◽

10.1007/s13237-021-00367-y ◽

2021 ◽

Author(s):

Gaurab Aditya Dhar ◽

Shagnik Saha ◽

Parama Mitra ◽

Ronita Nag Chaudhuri

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Regulation Of Gene Expression

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TET2 coactivates gene expression through demethylation of enhancers

Science Advances ◽

10.1126/sciadv.aau6986 ◽

2018 ◽

Vol 4 (11) ◽

pp. eaau6986 ◽

Cited By ~ 35

Author(s):

Lu Wang ◽

Patrick A. Ozark ◽

Edwin R. Smith ◽

Zibo Zhao ◽

Stacy A. Marshall ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Regulation Of Gene Expression ◽

Estrogen Receptor Α ◽

Dna Demethylation ◽

Estrogen Response ◽

Dna Base ◽

Modified Dna ◽

Global Increase ◽

Methylation Patterns

The tet methylcytosine dioxygenase 2 (TET2) enzyme catalyzes the conversion of the modified DNA base 5-methylcytosine to 5-hydroxymethylcytosine. TET2 is frequently mutated or dysregulated in multiple human cancers, and loss of TET2 is associated with changes in DNA methylation patterns. Here, using newly developed TET2-specific antibodies and the estrogen response as a model system for studying the regulation of gene expression, we demonstrate that endogenous TET2 occupies active enhancers and facilitates the proper recruitment of estrogen receptor α (ERα). Knockout of TET2 by CRISPR-CAS9 leads to a global increase of DNA methylation at enhancers, resulting in attenuation of the estrogen response. We further identified a positive feedback loop between TET2 and ERα, which further requires MLL3 COMPASS at these enhancers. Together, this study reveals an epigenetic axis coordinating a transcriptional program through enhancer activation via DNA demethylation.

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HIV-Associated Neurocognitive Disorder (HAND) Biomarker Identification: Significance Analysis of Microarrays and Two Persuasive Approaches with Random Forest

10.21203/rs.3.rs-19489/v1 ◽

2020 ◽

Author(s):

Hansapani Rodrigo ◽

Bryan Martinez ◽

Roberto De La Garza ◽

Upal Roy

Keyword(s):

Gene Expression ◽

White Matter ◽

Basal Ganglia ◽

Frontal Cortex ◽

Differentially Expressed ◽

Control Group ◽

Expression Levels ◽

Significance Analysis ◽

The Subject ◽

Gene Expression Levels

Abstract Background: HIV Associated Neurological Disorders (HAND) is relatively common among people with HIV-1 infection, even those taking combined antiretroviral treatment (cART). Genome-wide screening of transcription regulation in brain tissue helps in identifying substantial abnormalities present in patients’ gene transcripts and to discover possible biomarkers for HAND. This study explores the possibility of identifying differentially expressed (DE) genes, which can serve as potential biomarkers to detect HAND. In this study, we have investigated the gene expression levels of three subject groups with different impairment levels of HAND along with a control group in three distinct brain sectors: white matter, frontal cortex, and basal ganglia. Methods: Linear models with weighted least squares along with Benjamini-Hochberg multiple corrections were used to identify DE genes in each brain region. Genes with an adjusted p-value of less than 0.01 were identified as differentially expressed. Principal component analyses (PCA) were performed to detect any groupings among the subject groups. Significance Analysis of Microarrays (SAM) and random forests (RF) methods with two distinct approaches were used to identify DE genes. Results: A total of 710 genes in basal ganglia, 794 genes in the frontal cortex, and 1481 genes in white matter were screened. The highest proportion of DE genes was observed within the two brain regions, frontal neocortex, and basal ganglia. PCA analyses do not exhibit clear groupings among four subject groups. SAM and RF models reveal the genes, CIRBP, RBM3, GPNMB, ISG15, IFIT6, IFI6, and IFIT3, to have DE genes in the frontal cortex or basal ganglia among the subject groups. The gene, GADD45A, a protein-coding gene whose transcript levels tend to increase with stressful growth arrest conditions, was consistently ranked among the top genes by both RF models within the frontal cortex. Conclusions: Our study contributes to a comprehensive understanding of the gene expression levels of the subject with different severity levels of HAND. Several genes that appear to play critical roles in the inflammatory response have been found, and they have an excellent potential to be used as biomarkers to detect HAND under further investigations.

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Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

Human Molecular Genetics ◽

10.1093/hmg/ddz067 ◽

2019 ◽

Vol 28 (15) ◽

pp. 2477-2485 ◽

Cited By ~ 1

Author(s):

Diana A van der Plaat ◽

Judith M Vonk ◽

Natalie Terzikhan ◽

Kim de Jong ◽

Maaike de Vries ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Occupational Exposure ◽

Health Effects ◽

Mineral Dust ◽

Occupational Exposures ◽

Expression Levels ◽

Adverse Health Effects ◽

Never Smokers ◽

Gene Expression Levels

Abstract Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2×)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted.

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Association of intronic DNA methylation and hydroxymethylation alterations in the epigenetic etiology of dilated cardiomyopathy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00758.2018 ◽

2019 ◽

Vol 317 (1) ◽

pp. H168-H180 ◽

Cited By ~ 2

Author(s):

Ali M. Tabish ◽

Mohammed Arif ◽

Taejeong Song ◽

Zaher Elbeck ◽

Richard C. Becker ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Dilated Cardiomyopathy ◽

Cardiac Remodeling ◽

Rna Seq ◽

Wild Type ◽

Kegg Pathways ◽

Wild Type Phenotype ◽

Gene Expression Levels

In this study, we investigated the role of DNA methylation [5-methylcytosine (5mC)] and 5-hydroxymethylcytosine (5hmC), epigenetic modifications that regulate gene activity, in dilated cardiomyopathy (DCM). A MYBPC3 mutant mouse model of DCM was compared with wild type and used to profile genomic 5mC and 5hmC changes by Chip-seq, and gene expression levels were analyzed by RNA-seq. Both 5mC-altered genes (957) and 5hmC-altered genes (2,022) were identified in DCM hearts. Diverse gene ontology and KEGG pathways were enriched for DCM phenotypes, such as inflammation, tissue fibrosis, cell death, cardiac remodeling, cardiomyocyte growth, and differentiation, as well as sarcomere structure. Hierarchical clustering of mapped genes affected by 5mC and 5hmC clearly differentiated DCM from wild-type phenotype. Based on these data, we propose that genomewide 5mC and 5hmC contents may play a major role in DCM pathogenesis. NEW & NOTEWORTHY Our data demonstrate that development of dilated cardiomyopathy in mice is associated with significant epigenetic changes, specifically in intronic regions, which, when combined with gene expression profiling data, highlight key signaling pathways involved in pathological cardiac remodeling and heart contractile dysfunction.

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