2. Academic Validation
  3. Multidimensional mapping of stimulation-responsive regulatory elements and candidate causal variants in T cell activation

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

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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