Multidimensional mapping of stimulation-responsive regulatory elements and candidate causal variants in T cell...

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Genome-wide association studies (GWASs) have identified numerous noncoding variants associated with immune-related disorders.
• The precise mechanisms by which these noncoding variants exert their effects in a context-specific manner are not well understood.

Purpose of the Study:

• To investigate the dynamic regulatory mechanisms underlying genetic associations with immune-related disorders using CD4+ T cell activation as a model.
• To identify stimulation-responsive cis-regulatory elements (CREs) and key genes critical for T cell activation.

Main Methods:

• Applied a cistromic strategy to systematically identify and prioritize CREs and genes involved in T cell activation.
• Utilized capture Hi-C and tiling CRISPR activation screening at the CD28 locus.
• Investigated the role of ZNF384 in mediating chromatin looping and gene expression.

Main Results:

• Identified a pivotal CRE at the CD28 locus containing a causal insertion variant (rs5837875) that modulates CD28 activation in an allele-specific manner.
• Demonstrated that ZNF384 mediates stimulation-responsive chromatin looping between the enhancer and the CD28 promoter.
• Showed that this interaction leads to increased CD28 expression and T cell hyperactivation.

Conclusions:

• The study reveals a novel mechanism linking a noncoding variant to immune-related disorders through allele-specific modulation of CD28 expression and T cell hyperactivation.
• The developed integrative, context-dependent strategy provides a comprehensive framework for deciphering the regulatory mechanisms of complex diseases.
• Findings highlight the importance of studying noncoding variants in immune regulation and disease pathogenesis.