Identifying genetic variants associated with chromatin looping and genome function.

Area of Science:

• Genomics
• Immunology
• Epigenetics

Background:

• Understanding genetic regulation of gene expression is crucial in immunology.
• Chromatin conformation plays a key role in regulating gene activity.
• Previous studies focused on eQTLs and histone QTLs, but the role of chromatin contacts in genetic variation is less explored.

Purpose of the Study:

• To identify genetic variants associated with chromatin contact variations in naïve CD4 T cells.
• To explore the relationship between chromatin contact QTLs (iQTLs) and gene expression QTLs (eQTLs).
• To define novel QTLs, including connectivity-QTLs, and their impact on cell-specific gene expression.

Main Methods:

• Generated a comprehensive HiChIP dataset from 30 donors of naïve CD4 T cells (nCD4).
• Performed QTL mapping to identify iQTLs associated with genotype-dependent variation in HiChIP contacts.
• Integrated iQTL data with existing eQTL and histone QTL datasets, and GWAS variants.

Main Results:

• Identified numerous iQTLs in nCD4 cells, showing substantial overlap with known eQTLs and histone QTLs.
• Discovered a subset of nCD4 iQTLs that predict gene expression trends in memory CD4 T cell subsets.
• Defined connectivity-QTLs, linking genotype-dependent chromatin contact changes across broad genomic regions.

Conclusions:

• Chromatin contacts provide a complementary modality for QTL mapping.
• HiChIP-based iQTL analysis is powerful for discovering novel QTLs.
• This approach links genetic variation to cell-specific gene expression and regulatory network connectivity.