Shared and distinct molecular effects of regulatory genomic variants provide insight into mechanisms of distal enhancer-promoter communication

Abstract

Gene enhancers often form long-range contacts with promoters, but it remains unclear if enhancer activity and their chromosomal contacts are mediated by the same DNA sequences and recruited factors. We studied the effects of expression quantitative trait loci (eQTLs) on enhancer activity and promoter contacts in primary monocytes isolated from 34 individuals. Using eQTL-Capture Hi-C and a Bayesian approach considering both intra- and inter-individual variation, we initially detected 19 eQTLs associated with enhancer-eGene promoter contacts, most of which also associated with enhancer accessibility and activity. Capitalising on these shared effects, we devised a multi-modality Bayesian strategy, which identified 629 "trimodal QTLs" jointly associated with enhancer accessibility, eGene promoter contact, and gene expression. Causal mediation analysis and CRISPR interference revealed causal relationships between these three modalities. Many detected QTLs overlapped disease susceptibility loci and influenced the predicted binding of myeloid transcription factors, including SPI1, GABPB and STAT3. Additionally, a variant associated with PCK2 promoter contact directly disrupted a CTCF binding motif and impacted promoter insulation from downstream enhancers. Jointly, our findings suggest an inherent genetic link between the activity and connectivity of enhancers with relevance for human disease, and highlight the role of genetically-determined chromatin boundaries in gene control.