Chromatin interaction maps of active cis-regulatory elements in primary human immune cells reveal extensive overlap with disease-associated genetic variants

Abstract

Abstract Surveys of purified human immune cell types have revealed that common genetic variants have profound effects of gene expression in a highly cell-specific manner. However, it has been challenging to determine the mechanisms behind cell-specific regulatory effects as well as to pinpoint the potentially functional variants in dense haplotype blocks. Here, we performed genome-wide ChIP-Seq and proximity ligation-assisted ChIP-seq assays (HiChIP) for the H3K27ac modification to capture physical interactions between active cis-regulatory elements and their target gene promoters for 5 common and diverse immune cell types from 6 donors. The generated interaction maps identified long-range loops (over 20kb) for more than 90% of active cis-regulatory regions. We found that majority of the cis-regulatory interactions were highly cell-specific, which in turn correlated with cell-specific transcription factor binding motifs and gene expression patterns. Nearly 10% of expression quantitative trait loci (eQTLs), including disease-associated eQTLs and GWAS SNPs, were located at active cis-regulatory regions that interacted with the target genes of eQTLs (eGenes), thus allowing us to narrow down potentially functional/causative QTLs. Majority of cis-eQTLs that are specific to only a single cell type overlapped cis-regulatory elements that showed interactions with the promoter of their target eGenes only in that specific cell type. Our study thus provides a comprehensive interaction map of active regulatory elements for each of the 5 immune cell types across multiple donors and highlights the cell type-specificity of potentially functional variants and interactions linking them to genes in human disease.