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Epigenome-wide association of liver methylation patterns and complex metabolic traits in mice

ABSTRACT: Heritable epigenetic factors can contribute to complex disease etiology. In this study we examine, on a global scale, the contribution of DNA methylation to complex traits that are precursors to heart disease, diabetes and osteoporosis. We profiled DNA methylation patterns in the liver using bisulfite sequencing in 90 mouse inbred strains, genome-wide expression levels, proteomics, metabolomics and sixty-eight clinical traits, and performed epigenome-wide association studies (EWAS). We found associations with numerous clinical traits including bone mineral density, plasma cholesterol, insulin resistance, gene expression, protein and metabolite levels. A large proportion of associations were unique to EWAS and were not identified using GWAS. Methylation levels were regulated by genetics largely in cis, but we also found evidence of trans regulation, and we demonstrate that genetic variation in the methionine synthase reductase gene Mtrr affects methylation of hundreds of CpGs throughout the genome. Our results indicate that natural variation in methylation levels contributes to the etiology of complex clinical traits. Reduced representation bisulfite sequencing in mouse strains using liver genomic DNA

ORGANISM(S): Mus musculus

SUBMITTER: Luz Orozco

PROVIDER: E-GEOD-67507 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Epigenome-wide association of liver methylation patterns and complex metabolic traits in mice

Project description:Heritable epigenetic factors can contribute to complex disease etiology. In this study we examine, on a global scale, the contribution of DNA methylation to complex traits that are precursors to heart disease, diabetes and osteoporosis. We profiled DNA methylation patterns in the liver using bisulfite sequencing in 90 mouse inbred strains, genome-wide expression levels, proteomics, metabolomics and sixty-eight clinical traits, and performed epigenome-wide association studies (EWAS). We found associations with numerous clinical traits including bone mineral density, plasma cholesterol, insulin resistance, gene expression, protein and metabolite levels. A large proportion of associations were unique to EWAS and were not identified using GWAS. Methylation levels were regulated by genetics largely in cis, but we also found evidence of trans regulation, and we demonstrate that genetic variation in the methionine synthase reductase gene Mtrr affects methylation of hundreds of CpGs throughout the genome. Our results indicate that natural variation in methylation levels contributes to the etiology of complex clinical traits.

2015-04-02 | GSE67507 | GEO

In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse (Bisulfite-Seq)

Project description:Methylation of cytosines (5meC) is a widespread heritable DNA modification. During mammalian development, two global demethylation events are followed by waves of de novo DNA methylation. In vivo mechanisms of DNA methylation establishment are largely uncharacterized. Here we use Saccharomyces cerevisiae as a system lacking DNA methylation to define the chromatin features influencing the activity of the murine DNMT3B. Our data demonstrate that DNMT3B and H3K4 methylation are mutually exclusive and that DNMT3B is co-localized with H3K36 methylated regions. In support of this observation, DNA methylation analysis in yeast strains without Set1 and Set2 show an increase of relative 5meC levels at the TSS and a decrease in the gene-body, respectively. We extend our observation to the murine male germline, where H3K4me3 is strongly anti-correlated while H3K36me3 correlates with accelerated DNA methylation. These results show the importance of H3K36 methylation for gene-body DNA methylation in vivo. Collecting Yeast Whole Genome Bisulfite Sequencing Data

2015-04-02 | E-GEOD-66905 | biostudies-arrayexpress

Reduced representation bisulfite sequencing of liver DNA of 4-week old Bhmt-null mice (N=8) and wild type controls (N=8)

Project description:We measured the effect of methylation potential decrease, characteristic to the betaine homocysteine methyl-transferase (Bhmt) null mice, on liver DNA methylation patterns at 4 weeks. We used reduced representation bisulfite sequencing (RRBS) to measure DNA methylation differences in the livers of Bhmt-null and wild type mice (n= 8/group). We filtered sequencing data for CpGs with at least 10x coverage.

2020-09-18 | E-MTAB-5204 | biostudies-arrayexpress

Whole Genome Bisulfite Sequencing (WGBS) of cKIT+ sorted cells from 57-137 day old fetal testes and ovaries.

Project description:We performed WGBS analyses on 6 human fetal samples at 53-137 days of development, 4 female and 2 male. We show that methylation reprogramming in the human germline is global yet incomplete with exons, 3’UTRs and human-specific transposons remaining methylated. Whole Genome Bisulfite-Seq of cKIT+ cells analyzed from 4 biological samples for fetal ovaries from 57-113 days of development and 2 samples for fetal testes at 59 and 137 days of development.

2015-05-28 | E-GEOD-63393 | biostudies-arrayexpress

Serum Dioxin and DNA Methylation in the Sperm of Operation Ranch Hand Veterans Exposed to Agent Orange

Project description:Purpose: We studied dioxin exposures and DNA methylation in sperm in 37 men from the Air Force Health Study Methods: We compared methylation levels in subjects with no, low, medium, and high dioxin levels using EWAS and looking at regions of DNA. We compared our results to those from a Russian study Results: No loci were found to be significantly associated with dioxin exposure in the EWAS when controlling for false discovery rate. Region H19 was found to have significant associations. Five of our loci of interest overlapped with significant findings from the Russian study

2019-10-24 | GSE139307 | GEO

Epigenome-wide Association Study of Physical Activity and Physiological Parameters in Discordant Monozygotic Twins

Project description:An epigenome-wide association study (EWAS) was performed on buccal cells from monozygotic-twins (MZ) reared together as children, but who live apart as adults. Cohorts of twin pairs were used to investigate associations between neighborhood walkability and objectively measured physical activity (PA) levels. Due to dramatic cellular epigenetic sex differences, male and female MZ twin pairs were analyzed separately to identify differential DNA methylation regions (DMRs). A priori comparisons were made on MZ twin pairs discordant on body mass index (BMI), PA levels, and neighborhood walkability. In addition to direct comparative analysis to identify specific DMRs, a weighted gene coexpression network analysis (WGCNA) was performed to identify DNA methylation sites associated with the physiological traits of interest. The pairs discordant in PA levels had epigenetic alterations that correlated with reduced metabolic parameters (i.e., BMI). The DNA methylation sites are associated with over fifty genes previously found to be specific to vigorous PA, metabolic risk factors, and sex. Combined observations demonstrate that behavioral factors, such as physical activity, appear to promote systemic epigenetic alterations that impact metabolic risk factors. The epigenetic DNA methylation sites and associated genes identified provide insight into PA impacts on metabolic parameters and the etiology of obesity.

2022-12-01 | GSE216387 | GEO

Temporal stability and determinants of white blood cell DNA methylation in the Breakthrough Generations Study

Project description:Background: Epigenome-wide association studies (EWAS) using measurements of blood DNA methylation are performed to identify associations of methylation changes with environmental and lifestyle exposures, and with risk of developing disease. However, little is known about the variation of methylation markers in the population and their stability over time, both important factors in the design and interpretation of EWAS. Methods: We estimated the intraclass correlation coefficient (ICC) for each probe on the Illumina 450K methylation array in paired samples collected approximately six years apart from 92 participants in the Breakthrough Generations Study. We also evaluated relationships with age, reproductive and hormonal history, weight, alcohol intake and smoking. Results: Approximately 17% of probes on the 450K array had an ICC>0.50 and were considered stable variable methylated probes (stable-VMPs). Stable-VMPs were enriched for probes located in "shores" bordering CpG islands, and at approximately 1.3kb downstream from the transcription start site in the transition between the unmethylated promoter and methylated gene body. Both cross-sectional and longitudinal data analyses provided strong evidence for associations between changes in methylation levels and ageing. Smoking-related probes at 2q37.1 and AHRR were stable-VMPs and, as previously reported, related to time since quitting smoking. We also observed an excess of associations between methylation and weight changes beyond those expected by chance. Conclusion: Our results provide support for the use of WBC DNA methylation as a biomarker of exposure in EWAS. Larger studies, preferably with repeated measures over time, will be required to establish associations between specific probes and exposures.

2014-11-12 | GSE61151 | GEO

BS-seq of Arabidopsis pol2a mutants, of related mutants combinations and of WT and pol2a plants treated with hydroxyurea

Project description:DNA replication requires the faithful propagation of both genetic and epigenetic information. There is evidence that DNA polymerases play a role in transcriptional silencing, but the extent of their contribution and how it relates to heterochromatin maintenance is unclear. Analyzing a new hypomorphic pol2a mutant allele, we find that POL2A, the catalytic subunit of the DNA polymerase epsilon, maintains heterochromatin silencing and nuclear organization. Here, we profiled the DNA methylation landscape using BS-seq in various pol2a mutant alleles in Arabidopsis, in combination or not with other silencing and methyltransferase mutants. We also generated methylomes of wild-type and pol2a mutants exposed to hydroxyurea, to explore the consequences of replicative stress onto DNA methylation maintenance.

2020-06-04 | E-MTAB-8940 | biostudies-arrayexpress

Arabidopsis Root Methylation and Root Nucleosome Positioning

Project description:DNA methylation and nucleosome densities play a critical role in the regulation of gene expression. While much is known about the mechanisms of transcriptional control that are mediated by these, less is known about the degree to which they are tissue-specific. By comparing DNA methylation, nucleosome densities and transcriptional levels in different tissue types we can gain a clearer understanding of the extent to which these mechanisms influence gene expression in a tissue-specific manner. We compared DNA methylation in Arabidopsis shoots and roots and found extensive differences across the genome. We computed DNA methylation differences between roots and shoots at single cytosines and found that one in every 173 cytosines was differentially methylated. In addition, we compared DNA methylation with tissue-specific gene expression and nucleosome density measurements to identify associations between these. We also identified a group of genes that are strongly correlated with these epigenetic marks and are significantly differentially methylated between roots and shoots. These root-specific genes are part of the extensin family, and are preferentially methylated and have at least 10-fold higher expression and lower nucleosome density in roots relative to shoots. No replicates, two libraries for root methylation.

2014-02-11 | E-GEOD-52762 | biostudies-arrayexpress

Scl specifies hemogenic endothelium and inhibits cardiogenesis via primed enhancers [RRBS]

Project description:Scl/Tal1 confers hemogenic competence and prevents cardiomyogenesis in embryonic endothelium. Here we show that Scl both directly activates a broad gene regulatory network required for hematopoietic stem/progenitor cell (HS/PC) development, and represses transcriptional regulators required for cardiogenesis. Cardiac repression occurs during a short developmental window through Scl binding to distant cardiac enhancers that harbor H3K4me1 at this stage. Scl binding to hematopoietic regulators extends throughout HS/PC and erythroid development and spreads from distant enhancers to promoters. Surprisingly, Scl complex partners Gata 1 and 2 are dispensable for hematopoietic versus cardiac specification and Scl binding to the majority of its target genes. Nevertheless, Gata factors co-operate with Scl to activate selected transcription factors to facilitate HS/PC emergence from hemogenic endothelium. These results uncover a dual function for Scl in dictating hematopoietic versus cardiac fate choice and suggest a mechanism by which lineage-specific bHLH factors direct the divergence of competing fates. Examination of Scl and Gata 1 & 2 target genes in ES cell derived day4.75 EB (embryoid body) Tie2+CD31+CD41- endothelial cells

2015-01-01 | E-GEOD-56359 | biostudies-arrayexpress

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