Multidimensional mapping of stimulation-responsive regulatory elements and candidate causal variants in T cell activation | Science Advances

Abstract

Genome-wide association studies (GWASs) have elucidated numerous noncoding variants linked to immune-related disorders, yet the intricate context-specific mechanisms governing their effects remain poorly defined. Here, we leverage CD4

⁺

T cell activation as a model to integrate multilayered genomic data and interrogate the dynamic regulatory mechanisms underpinning these genetic associations. We have applied a cistromic strategy to systematically identify and prioritize stimulation-responsive cis–regulatory elements (CREs) and key genes essential for T cell activation. Using capture Hi-C and tiling CRISPR activation screening at the

CD28

locus, we reveal a pivotal CRE harboring a causal small insertion variant, rs5837875, that modulates

CD28

activation in an allele-specific manner. Mechanistically, we demonstrate that ZNF384 mediates stimulation-responsive chromatin looping between the rs5837875-containing enhancer and the

CD28

promoter, culminating in heightened

CD28

expression and aberrant T cell hyperactivation. Our integrative and context-dependent strategy establishes a comprehensive pathway for deciphering the missing regulatory mechanisms of complex disease.

مصدر