Enhancer connectome in primary human cells reveals target genes of disease-associated DNA elements

The imprecision of linking intergenic mutations to target genes has limited molecular understanding of diverse human diseases. Here, we show H3K27ac HiChIP generates high-resolution contact maps of active enhancers and target genes in rare primary human T cell subtypes and coronary artery smooth muscle cells. Differentiation of naïve T cells to either T helper 17 cells or regulatory T cells create subtype-specific enhancer-promoter interactions, specifically at regions of shared DNA accessibility. We provide an atlas for assigning molecular functions to autoimmune and cardiovascular disease risk variants, linking hundreds of noncoding variants to putative gene targets. HiChIP target genes are supported by CRISPR interference and activation of enhancers, expression quantitative trait loci, and allele-specific enhancer loops in patient-derived primary cells. The majority of disease-associated enhancers contact genes beyond the nearest gene in the linear genome, leading to a four-fold expansion of target genes for autoimmune and cardiovascular diseases. Overall design: Low cell number titration H3K27ac HiChIP in mESC. H3K27ac HiChIP and ATAC-seq in primary sorted Naïve, Th17, and Treg cells. H3K27ac HiChIP in GM12878, K562, My-La, and phased HCASMC cells.