An autoimmune pleiotropic SNP modulates IRF5 alternative promoter usage through ZBTB3-mediated chromatin looping

Zhao Wang (), Qian Liang, Xinyi Qian, Bolang Hu, Zhanye Zheng, Jianhua Wang, Yuelin Hu, Zhengkai Bao, Ke Zhao, Yao Zhou, Xiangling Feng, Xianfu Yi, Jin Li, Jiandang Shi, Zhe Liu, Jihui Hao, Kexin Chen, Ying Yu, Pak Chung Sham, Wange Lu, Xiaoyan Wang (), Weihong Song () and Mulin Jun Li ()
Additional contact information
Zhao Wang: Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University
Qian Liang: Tianjin Medical University
Xinyi Qian: Tianjin Medical University
Bolang Hu: Wenzhou Medical University
Zhanye Zheng: Tianjin Medical University
Jianhua Wang: Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University
Yuelin Hu: Wenzhou Medical University
Zhengkai Bao: Wenzhou Medical University
Ke Zhao: Tianjin Medical University
Yao Zhou: Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University
Xiangling Feng: Tianjin Medical University
Xianfu Yi: Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University
Jin Li: Tianjin Medical University
Jiandang Shi: Nankai University
Zhe Liu: Tianjin Medical University
Jihui Hao: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy
Kexin Chen: Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University
Ying Yu: Tianjin Medical University
Pak Chung Sham: The University of Hong Kong
Wange Lu: Nankai University
Xiaoyan Wang: Central South University Changsha
Weihong Song: Wenzhou Medical University
Mulin Jun Li: Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: Abstract Genetic sharing is extensively observed for autoimmune diseases, but the causal variants and their underlying molecular mechanisms remain largely unknown. Through systematic investigation of autoimmune disease pleiotropic loci, we found most of these shared genetic effects are transmitted from regulatory code. We used an evidence-based strategy to functionally prioritize causal pleiotropic variants and identify their target genes. A top-ranked pleiotropic variant, rs4728142, yielded many lines of evidence as being causal. Mechanistically, the rs4728142-containing region interacts with the IRF5 alternative promoter in an allele-specific manner and orchestrates its upstream enhancer to regulate IRF5 alternative promoter usage through chromatin looping. A putative structural regulator, ZBTB3, mediates the allele-specific loop to promote IRF5-short transcript expression at the rs4728142 risk allele, resulting in IRF5 overactivation and M1 macrophage polarization. Together, our findings establish a causal mechanism between the regulatory variant and fine-scale molecular phenotype underlying the dysfunction of pleiotropic genes in human autoimmunity.

Date: 2023
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DOI: 10.1038/s41467-023-36897-z

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