Dataset Information

ChIP-sequencing for histone modifications in primary human hepatocytes from three individuals heterozygous for the T2D risk haplotype at the SLC16A11 locus

ABSTRACT: ChIP-sequencing for H3K4me1, H3K4me3, and H3K27ac was performed in primary human hepatocytes from three individuals heterozygous for the T2D risk haplotype at the SLC16A11 locus. The goal was to identify allelic skews in chromatin marks at variants at the SLC16A11 locus.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99301 | GEO | 2017/06/29

SECONDARY ACCESSION(S): PRJNA388467

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:The 9p21.3 cardiovascular disease locus is the most influential common genetic risk factor for coronary artery disease, accounting for ~10-15% of disease among non-African populations. The ~60kb risk haplotype is human-specific and lacks coding genes, hindering efforts to decipher its function. Genetic studies implicate the 9p21.3 locus and other risk genes to effects in the vascular wall. Here, we use genome editing to delete the entire risk on non-risk haplotype from the genomes of human iPSCs and perform genomewide transcriptional profiling along the timecourse of their differentiation into vascular smooth muscle cells (VSMCs). These studies identify a network of ~3000 genes governed by the risk haplotype in VSMCs that predict deficits in cell division, adhesion and contraction, which we confirmufunctionally. Remarkably, deleting the risk haplotype reverts VSMCs to resemble the non-risk VSMCs, suggesting that the risk region drives a cell state transition. transcriptionally and functionally. . Deleting the risk haplotype reverts these cells to reverted to the non-risk of iPSCs we show that the non-risk haplotype has little effect on locus we produce iPSCs from risk and non-risk individuals, delete each haplotype using genome editing and generate vascular smooth muscle cells (VSMCs). We show that risk VSMCs exhibit aberrant adhesion and contraction, concomitant with dramatically altered global transcriptional changes that are enriched in previously identified cardiovascular disease genes and pathways. Unexpectedly, deleting the risk haplotype rescues VSMC transcriptional identity and function, while expressing the 9p21.3-associated long non-coding RNA ANRIL induces risk phenotypes in non-risk VSMCs. This studies shows that the risk haplotype dominantly predisposes VSMCs to adopt perturbed phenotypes associated with cardiovascular disease and establishes haplotype-edited iPSCs as powerful tools for functionally annotating human-specific variation in non-coding genomic regions.

Project description:A major goal of genetics research is to elucidate mechanisms explaining how genetic variation contributes to phenotypic variation. The genetic variants identified in genome-wide association studies (GWASs) generally explain only a small proportion of heritability of phenotypic traits, the so-called missing heritability problem. Recent evidence suggests that additional common variants beyond lead GWAS variants contribute to phenotypic variation; however, their mechanistic underpinnings generally remain unexplored. Herein, we undertake a study of haplotype-specific mechanisms of gene regulation at 8p23.1 in the human genome, a region associated with a number of complex diseases. The FAM167A-BLK locus in this region has been consistently found in the genome-wide association studies (GWASs) of systemic lupus erythematosus (SLE) in all major ancestries. Our haplotype-specific chromatin interaction (Hi-C) experiments, allele-specific enhancer activity measurements, genetic analyses, and epigenome editing experiments revealed that: (1) haplotype-specific long-range chromatin interactions are prevalent in 8p23.1; (2) BLK promoter and cis-regulatory elements cooperatively interact with haplotype-specificity; (3) genetic variants at distal regulatory elements are allele-specific modifiers of the promoter variants at FAM167A-BLK; (4) the BLK promoter interacts with and, as an enhancer-like promoter, regulates FAM167A expression and (5) local allele-specific enhancer activities are influenced by global haplotype structure due to chromatin looping. Although SLE causal variants at the FAM167A-BLK locus are thought to reside in the BLK promoter region, our results reveal that genetic variants at distal regulatory elements modulate promoter activity, changing BLK and FAM167A gene expression and disease risk. Our results suggest that global haplotype-specific 3-dimensional chromatin looping architecture has a strong influence on local allelic BLK and FAM167A gene expression, providing mechanistic details for how regional variants controlling the BLK promoter may influence disease risk.

Dataset Information

ChIP-sequencing for histone modifications in primary human hepatocytes from three individuals heterozygous for the T2D risk haplotype at the SLC16A11 locus

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets