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

  • Sci Adv. 2026 Jan 2;12(1):eady2539. doi: 10.1126/sciadv.ady2539.
Zhao Wang  1  2 ,  Wei Dong  3 ,  Xiangling Feng  2 ,  Xinran Xu  2 ,  Yao An  1 ,  Huiling Xiao  1 ,  Menghan Luo  2 ,  Qian Liang  1 ,  Ruoxuan Bai  1 ,  Ke Zhao  4 ,  Liuxing Wu  2 ,  Lin Zhao  2 ,  Yao Zhou  3 ,  Xianfu Yi  2 ,  Dandan Huang  4 ,  Kaustav Sengupta  5 ,  Dariusz Plewczynski  5 ,  Pak Chung Sham  6 ,  Chao Liu  3 ,  Yang Yu  3 ,  Wei Li  3 ,  Qing Gong  7 ,  Weihong Song  1 ,  Wenhao Zhou  3 ,  Mulin Jun Li  2  3
Affiliations
  • 1. Oujiang Laboratory, Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
  • 2. State Key Laboratory of Experimental Hematology, Department of Bioinformatics, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 3. Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
  • 4. Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 5. Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland.
  • 6. Centre for PanorOmic Sciences-Genomics and Bioinformatics Cores, The University of Hong Kong, Hong Kong, China.
  • 7. GMU-GIBH Joint School of Life Science, Guangzhou Medical University, Guangzhou, China.
PMID: 41477821 DOI: 10.1126/sciadv.ady2539
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.

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