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

Area of Science:

• Genomics
• Epigenetics
• Immunology

Background:

• Expression quantitative trait loci (eQTLs) link genetic variants to gene expression but lack functional specificity.
• Identifying functionally important eQTLs and their regulatory mechanisms remains a challenge.

Purpose of the Study:

• To develop a method for identifying functionally important eQTLs (pieQTLs) by integrating HiChIP data with gene expression.
• To investigate the cell-type-specific regulatory mechanisms of eQTLs.
• To discover novel eQTLs, including long-distance and disease-associated variants.

Main Methods:

• Utilized H3K27ac HiChIP assays to map active cis-regulatory elements and their interactions with gene promoters in five immune cell types.
• Developed a novel eQTL discovery approach using HiChIP-based promoter interaction maps to guide SNP selection.
• Employed reporter assays, CRISPRi, dCas9-tiling, and base-pair editing for functional validation of pieQTLs.

Main Results:

• Identified promoter-interacting eQTLs (pieQTLs) overlapping active cis-regulatory elements in immune cells.
• Demonstrated cell-type-specific mechanisms underlying eQTL regulation.
• Discovered ultra-long-distance pieQTLs (>1 megabase), including several disease-risk variants, validated through functional assays.

Conclusions:

• The developed pieQTL approach enhances functional eQTL discovery beyond conventional methods.
• Noncoding variants play a crucial role in cell-specific gene regulation and disease association.
• This study provides insights into the functional relevance of noncoding variants in complex diseases.