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Methylation QTLs are associated with coordinated changes in transcription factor binding, histone modifications, and gene expression levels

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. DNA methylation is an important epigenetic regulator of gene expression. Recent studies have revealed widespread associations between genetic variation and methylation levels. However, the mechanistic links between genetic variation and methylation remain unclear. To begin addressing this gap, we collected methylation data at ~300,000 loci in lymphoblastoid cell lines (LCLs) from 64 HapMap Yoruba individuals, and genome-wide bisulfite sequence data in ten of these individuals. We identified (at an FDR of 10%) 13,915 *cis* methylation QTLs (meQTLs), i.e., CpG sites in which changes in DNA methylation are associated with genetic variation at proximal loci. We found that meQTLs are frequently associated with changes in methylation at multiple CpGs across regions of up to 3 kb. Interestingly, meQTLs are also frequently associated with variation in other properties of gene regulation, including histone modifications, DNase I accessibility, chromatin accessibility, and expression levels of nearby genes. These observations suggest that genetic variants may lead to coordinated molecular changes in all of these regulatory phenotypes. One plausible driver of coordinated changes in different regulatory mechanisms is variation in transcription factor (TF) binding. Indeed, we found that SNPs that change predicted TF binding affinities are significantly enriched for associations with DNA methylation at nearby CpGs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57483 | GEO | 2014/05/09

SECONDARY ACCESSION(S): PRJNA246535

REPOSITORIES: GEO

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Methylation QTLs are associated with coordinated changes in transcription factor binding, histone modifications, and gene expression levels [Bisulfite-Seq]

Project description:DNA methylation is an important epigenetic regulator of gene expression. Recent studies have revealed widespread associations between genetic variation and methylation levels. However, the mechanistic links between genetic variation and methylation remain unclear. To begin addressing this gap, we collected methylation data at ~300,000 loci in lymphoblastoid cell lines (LCLs) from 64 HapMap Yoruba individuals, and genome-wide bisulfite sequence data in ten of these individuals. We identified (at an FDR of 10%) 13,915 *cis* methylation QTLs (meQTLs), i.e., CpG sites in which changes in DNA methylation are associated with genetic variation at proximal loci. We found that meQTLs are frequently associated with changes in methylation at multiple CpGs across regions of up to 3 kb. Interestingly, meQTLs are also frequently associated with variation in other properties of gene regulation, including histone modifications, DNase I accessibility, chromatin accessibility, and expression levels of nearby genes. These observations suggest that genetic variants may lead to coordinated molecular changes in all of these regulatory phenotypes. One plausible driver of coordinated changes in different regulatory mechanisms is variation in transcription factor (TF) binding. Indeed, we found that SNPs that change predicted TF binding affinities are significantly enriched for associations with DNA methylation at nearby CpGs. Whole genomic DNA from 10 Yoruba HapMap individuals and spiked in unmethylated lambda phage DNA was bisuflite converted using the Invitrogen MethylCode Bisulfite Conversion Kit and sequenced using a Illumina HiSeq 2000

2014-05-09 | E-GEOD-57471 | biostudies-arrayexpress

Methylation QTLs are associated with coordinated changes in transcription factor binding, histone modifications, and gene expression levels [Bisulfite-array]

Project description:DNA methylation is an important epigenetic regulator of gene expression. Recent studies have revealed widespread associations between genetic variation and methylation levels. However, the mechanistic links between genetic variation and methylation remain unclear. To begin addressing this gap, we collected methylation data at ~300,000 loci in lymphoblastoid cell lines (LCLs) from 64 HapMap Yoruba individuals, and genome-wide bisulfite sequence data in ten of these individuals. We identified 11,752 methylation QTLs (meQTLs)—i.e., loci in which genetic variation is significantly associated with changes in DNA methylation. We found that meQTLs are frequently associated with changes in methylation at multiple CpGs across regions of up to 3 kb. Interestingly, meQTLs are also frequently associated with variation in other properties of gene regulation, including histone modifications, DNaseI accessibility, chromatin accessibility, and expression levels of nearby genes. These observations suggest a shared and coordinated molecular variation in all of these regulatory phenotypes. One plausible driver of coordinated changes in different regulatory mechanisms is variation in transcription factor (TF) binding. Indeed, we found that both changes in putative TF binding affinity and changes in the strength of TF binding footprints are associated with variation in DNA methylation near the TF binding sites. Considered together, our observations are consistent with a model whereby changes in TF binding may frequently drive coordinated changes in DNA methylation, histone modification, and gene expression levels. Bisulfite converted DNA from 64 individuals was hybridized to the Illumina Infinium HumanMethylation450 BeadChip

2014-05-09 | E-GEOD-57481 | biostudies-arrayexpress

Methylation QTLs are associated with coordinated changes in transcription factor binding, histone modifications, and gene expression levels [Bisulfite-array]

2014-05-09 | GSE57481 | GEO

Methylation QTLs are associated with coordinated changes in transcription factor binding, histone modifications, and gene expression levels [Bisulfite-Seq]

2014-05-09 | GSE57471 | GEO

Exploring the Genetic Basis of Human Population Differences in DNA Methylation and their Causal Impact on Immune Gene Regulation

Project description:Background: DNA methylation is influenced by both environmental and genetic factors and is increasingly thought to affect variation in complex traits and diseases. Yet, the extent of ancestry-related differences in DNA methylation, its genetic determinants, and their respective causal impact on immune gene regulation remain elusive. Results: We report extensive population differences in DNA methylation between 156 individuals of African and Europeandescent —detected in primary monocytes that were used as a model of a major innate immunity cell type. Most of these differences (~70%) were driven by DNA sequence variants nearby CpG sites (meQTLs), which account for ~60% of the variance in DNA methylation. We also identify several master regulators of DNA methylation variation in trans, including a regulatory hub nearby the transcription factor-encoding CTCF gene, which contributes markedly to ancestry-related differences in DNA methylation. Furthermore, we establish that variationin DNA methylation isassociated with varying gene expression levelsfollowing mostly, but not exclusively, a canonical model of negative associations, particularly in enhancer regions. Specifically, we find that DNA methylation highly correlates with transcriptional activity of 811 and 230 genes, at the basal state and upon immune stimulation, respectively. Finally, using a Bayesian approach, we estimate causal mediation effects of DNA methylation on gene expression in ~20% of the studied cases, indicating that DNA methylation can play an active role in immune gene regulation. Conclusion: Using a system-level approach, our study reveals substantial ancestry-related differences in DNA methylation and provides evidence for their causal impact on immune gene regulation.

2018-10-30 | GSE120610 | GEO

Mapping DNA methylation across development, genotype, and schizophrenia in the human frontal cortex

Project description:DNA methylation (DNAm) is important in brain development, and potentially in schizophrenia. We characterized DNAm in prefrontal cortex from 335 non-psychiatric controls across the lifespan and 191 patients with schizophrenia, and identified widespread changes in the transition from prenatal to postnatal life. These DNAm changes manifest in the transcriptome, correlate strongly with a shifting cellular landscape, and overlap regions of genetic risk for schizophrenia. A quarter of published GWAS-suggestive loci (4,208/15,930, p<10-20) manifest as significant methylation quantitative trait loci (meQTLs), including 59.6% of GWAS-positive schizophrenia loci. We identified 2,104 CpGs that differ between schizophrenia patients and controls, enriched for genes related to development and neurodifferentiation. The schizophrenia-associated CpGs strongly correlate with changes related to the prenatal-postnatal transition and show slight enrichment for GWAS risk loci, while not corresponding to CpGs differentiating adolescence from later adult life. These data implicate an epigenetic component to the developmental origins of this disorder.

2015-10-21 | GSE74193 | GEO

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. Reduced representation bisulfite sequencing in mouse strains using liver genomic DNA

2015-04-02 | E-GEOD-67507 | biostudies-arrayexpress

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

2015-04-02 | GSE67507 | GEO

Analyzing whole genome bisulfite sequencing data from highly divergent genotypes

Project description:In the study of DNA methylation, genetic variation between species, strains, or individuals can result in CpG sites that are exclusive to a subset of samples, and insertions and deletions can rearrange the spatial distribution of CpGs. How to account for this variation in an analysis of the interplay between sequence variation and DNA methylation is not well understood, especially when the number of CpG differences between samples is large. Here we use whole-genome bisulfite sequencing data on two highly divergent mouse strains to study this problem. We show that alignment to personal genomes is necessary for valid methylation quantification. We introduce a method for including strain-specific CpGs in differential analysis, and show that accounting for strain-specific CpGs increases power. Our method uses smoothing to impute methylation levels at strain-specific sites, thereby allowing strain-specific CpGs to contribute to the analysis, and also allowing us to account for differences in the spatial occurrences of CpGs. Our results have implications for joint analysis of genetic variation and DNA methylation using bisulfite-converted DNA, and unlocks the use of personal genomes for addressing this question.

2019-05-14 | GSE87101 | GEO

Mapping of variable DNA methylation across multiple cell types defines a dynamic regulatory landscape of the human genome

Project description:DNA methylation is an important epigenetic modification involved in many biological processes and diseases. Many studies have mapped DNA methylation changes associated with embryogenesis, cell differentiation and cancer at a genome-wide scale. Our understanding of genome-wide DNA methylation changes in a developmental or disease-related context has been steadily growing. However, the investigation of which CpGs are variably methylated in different normal cell or tissue types is still limited. Here we present an in-depth analysis of 54 single-CpG-resolution DNA methylomes of normal human cell types by integrating high-throughput sequencing-based methylation data. We find that the percentage of unmethylated CpGs is relatively fixed regardless of cell type. However, which CpGs are unmethylated is cell-type specific. We categorize the 26 million human autosomal CpGs based on their methylation levels across multiple cell types to identify variably methylated CpGs. Among all the autosomal CpGs, 22.6% exhibit variable DNA methylation across cell types included in our study. These variably methylated CpGs form 66 thousand variably methylated regions (VMRs), encompassing 11% of the genome. By integrating a multitude of genomic data, we found that VMRs enrich for histone modifications indicative of enhancers, suggesting their role as regulatory elements marking cell type specificity. VMRs enrich for transcription factor binding sites in a tissue-dependent manner. Importantly, they enrich for GWAS variants, suggesting VMRs could potentially be implicated in disease and complex traits. Taken together, our results highlight the link among CpG methylation variation, genetic variation and disease risk in a tissue-specific manner for many human cell types. Processed data includes new Samples and 75 Samples from GSE16368 and 2 Samples from GSE51565.

2016-04-06 | E-GEOD-69894 | biostudies-arrayexpress

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