Promoter-interacting expression quantitative trait loci are enriched for functional genetic variants

H3K27ac HiChIP analysis helps to identify promoter-interacting expression quantitative trait loci (pieQTLs) in five common immune cell types. Some pieQTLs overlap with nontranscribed promoters that act as enhancers. Expression quantitative trait loci (eQTLs) studies provide associations of genetic variants with gene expression but fall short of pinpointing functionally important eQTLs. Here, using H3K27ac HiChIP assays, we mapped eQTLs overlapping active cis-regulatory elements that interact with their target gene promoters (promoter-interacting eQTLs, pieQTLs) in five common immune cell types (Database of Immune Cell Expression, Expression quantitative trait loci and Epigenomics (DICE) cis-interactome project). This approach allowed us to identify functionally important eQTLs and show mechanisms that explain their cell-type restriction. We also devised an approach to eQTL discovery that relies on HiChIP-based promoter interaction maps as a structural framework for deciding which SNPs to test for association with gene expression, and observe ultra-long-distance pieQTLs (>1 megabase away), including several disease-risk variants. We validated the functional role of pieQTLs using reporter assays, CRISPRi, dCas9-tiling guides and Cas9-mediated base-pair editing. In this article we present a method for functional eQTL discovery and provide insights into relevance of noncoding variants for cell-specific gene regulation and for disease association beyond conventional eQTL mapping.

Automated summary

This study utilized H3K27ac HiChIP analysis to identify promoter-interacting expression quantitative trait loci (pieQTLs) in five common immune cell types, showing the importance of these variants in gene regulation. Additionally, the study presents a method for functional eQTL discovery and provides insights into the relevance of noncoding variants for cell-specific gene regulation and disease association.