Genetic coupling of enhancer activity and connectivity in gene expression control

Area of Science:

• Genomics
• Epigenetics
• Molecular Biology

Background:

• Gene enhancers regulate gene expression through long-range DNA interactions with promoters.
• The precise DNA sequences and factors mediating enhancer activity and chromosomal contacts are not fully understood.

Purpose of the Study:

• To investigate the impact of expression quantitative trait loci (eQTLs) on enhancer activity and promoter contacts.
• To identify genetic variants that jointly influence enhancer accessibility, promoter looping, and gene expression.

Main Methods:

• Utilized eQTL-Capture Hi-C in primary human monocytes.
• Applied Bayesian and multi-modality Bayesian approaches to analyze genetic associations.
• Employed causal mediation analysis and CRISPR interference for functional validation.

Main Results:

• Identified 19 eQTLs associated with enhancer-promoter contacts, accessibility, and activity.
• Discovered 629 "trimodal QTLs" jointly affecting enhancer accessibility, promoter contact, and gene expression.
• Demonstrated causal relationships between these regulatory elements and identified variants influencing transcription factor binding and chromatin boundaries.

Conclusions:

• Genetic variation inherently couples enhancer activity and DNA connectivity to control gene expression.
• Findings highlight the role of genetically determined chromatin boundaries in gene regulation and human disease susceptibility.