Haplotype-specific chromatin looping reveals genetic interactions of regulatory regions modulating gene expression in 8p23.1.

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 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) promoter and -regulatory elements cooperatively interact with haplotype-specificity; 3) genetic variants at distal regulatory elements are allele-specific modifiers of the promoter variants at ; 4) the promoter interacts with and, as an enhancer-like promoter, regulates expression and 5) local allele-specific enhancer activities are influenced by global haplotype structure due to chromatin looping. Although systemic lupus erythematosus causal variants at the locus are thought to reside in the promoter region, our results reveal that genetic variants at distal regulatory elements modulate promoter activity, changing and gene expression and disease risk. Our results suggest that global haplotype-specific 3-dimensional chromatin looping architecture has a strong influence on local allelic and gene expression, providing mechanistic details for how regional variants controlling the promoter may influence disease risk.