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Identification of genetic variants that affect histone modifications in human cells

ABSTRACT: Histone modifications are important markers of function and chromatin state, yet the DNA elements that direct them to specific locations in the genome are poorly understood. Here we use the genetic variation in Yoruba lymphoblastoid cell lines as a natural experiment to identify genetic differences that affect histone marks and to better understand their relationship with transcriptional regulation. Across the genome, we identified hundreds of quantitative trait loci that impact histone modification or RNA polymerase (PolII) occupancy. In many cases the same variant is associated with quantitative changes in multiple histone marks and PolII, as well as in DNaseI sensitivity and nucleosome positioning, indicating that these molecular phenotypes often share a single underlying genetic cause. Variants that impact chromatin at distal regulatory sites frequently also direct changes in chromatin and gene expression at associated promoters; while most of these distal regulators enhance promoter activity, some act as distal chromatin silencers. Finally, we find that polymorphisms in transcription factor binding sites are often causally responsible for variation in local histone modification. In summary, the class of variants identified here generate coordinated changes in chromatin both locally and sometimes at distant locations, frequently drive changes in gene expression, and likely play an important role in the genetics of complex traits.

ORGANISM(S): Homo sapiens

PROVIDER: GSE47991 | GEO | 2013/10/01

SECONDARY ACCESSION(S): PRJNA208589

REPOSITORIES: GEO

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Identification of genetic variants that affect histone modifications in human cells

Project description:Histone modifications are important markers of function and chromatin state, yet the DNA elements that direct them to specific locations in the genome are poorly understood. Here we use the genetic variation in Yoruba lymphoblastoid cell lines as a natural experiment to identify genetic differences that affect histone marks and to better understand their relationship with transcriptional regulation. Across the genome, we identified hundreds of quantitative trait loci that impact histone modification or RNA polymerase (PolII) occupancy. In many cases the same variant is associated with quantitative changes in multiple histone marks and PolII, as well as in DNaseI sensitivity and nucleosome positioning, indicating that these molecular phenotypes often share a single underlying genetic cause. Variants that impact chromatin at distal regulatory sites frequently also direct changes in chromatin and gene expression at associated promoters; while most of these distal regulators enhance promoter activity, some act as distal chromatin silencers. Finally, we find that polymorphisms in transcription factor binding sites are often causally responsible for variation in local histone modification. In summary, the class of variants identified here generate coordinated changes in chromatin both locally and sometimes at distant locations, frequently drive changes in gene expression, and likely play an important role in the genetics of complex traits. ChIP-seq of RNA Polymerase II and 4 histone modifications (H3K4me1, H3K4me3, H3K27ac, H3K27me3) in 10 unrelated Yoruba HapMap lymphoblastoid cell lines

2013-10-01 | E-GEOD-47991 | biostudies-arrayexpress

Genetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions

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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

Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for EP300 dependent activation and repression of transcription.

Project description:The ARID1A subunit of the SWI/SNF chromatin remodelling complex is one of the most frequently mutated tumour suppressors. Here, a degron system is applied to detect rapid loss of chromatin accessibility at thousands of loci that frequently include binding sites for pluripotency transcription factors where ARID1A acts to generate accessible mini domains of nucleosomes. At a subset of these locations, the histone acetyltransferase EP300 dissociates and histone H3K27 acetylation decreases. Genes adjacent to these sites are frequently downregulated. Remarkably, dissociation of EP300 in the absence of chromatin changes is linked to rapid transcriptional upregulation. Sites where EP300 exhibits co-repressor activity are enriched for MLL3-4, BRD4 and RNA polymerase. A few genes directly affected by these pathways are associated with cancer and pluripotency pathways that come to dominate the chronic ARID1A phenotype. This suggests a handful of upstream regulators drive adaption and represent new sites for intervention in ARID1A driven diseases.

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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

Project description: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.

2014-05-09 | GSE57483 | GEO

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