SLE non-coding genetic risk variant determines the epigenetic dysfunction of an immune cell specific enhancer that controls disease-critical microRNA expression

Guojun Hou, Isaac T. W. Harley, Xiaoming Lu, Tian Zhou, Ning Xu, Chao Yao, Yuting Qin, Ye Ouyang, Jianyang Ma, Xinyi Zhu, Xiang Yu, Hong Xu, Dai Dai, Huihua Ding, Zhihua Yin, Zhizhong Ye, Jun Deng, Mi Zhou, Yuanjia Tang, Bahram Namjou, Ya Guo, Matthew T. Weirauch, Leah C. Kottyan, John B. Harley and Nan Shen ()
Additional contact information
Guojun Hou: Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM)
Isaac T. W. Harley: Cincinnati Children’s Hospital Medical Center
Xiaoming Lu: Cincinnati Children’s Hospital Medical Center
Tian Zhou: Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM)
Ning Xu: Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM)
Chao Yao: University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS)
Yuting Qin: Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM)
Ye Ouyang: Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM)
Jianyang Ma: Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM)
Xinyi Zhu: Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM)
Xiang Yu: Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM)
Hong Xu: Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM)
Dai Dai: Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM)
Huihua Ding: Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM)
Zhihua Yin: Shenzhen Futian Hospital for Rheumatic Diseases
Zhizhong Ye: Shenzhen Futian Hospital for Rheumatic Diseases
Jun Deng: Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM)
Mi Zhou: Shanghai Jiao Tong University (SJTU)
Yuanjia Tang: Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM)
Bahram Namjou: Cincinnati Children’s Hospital Medical Center
Ya Guo: Shanghai Jiao Tong University (SJTU)
Matthew T. Weirauch: Cincinnati Children’s Hospital Medical Center
Leah C. Kottyan: Cincinnati Children’s Hospital Medical Center
John B. Harley: Cincinnati Children’s Hospital Medical Center
Nan Shen: Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM)

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract Since most variants that impact polygenic disease phenotypes localize to non-coding genomic regions, understanding the consequences of regulatory element variants will advance understanding of human disease mechanisms. Here, we report that the systemic lupus erythematosus (SLE) risk variant rs2431697 as likely causal for SLE through disruption of a regulatory element, modulating miR-146a expression. Using epigenomic analysis, genome-editing and 3D chromatin structure analysis, we show that rs2431697 tags a cell-type dependent distal enhancer specific for miR-146a that physically interacts with the miR-146a promoter. NF-kB binds the disease protective allele in a sequence-specific manner, increasing expression of this immunoregulatory microRNA. Finally, CRISPR activation-based modulation of this enhancer in the PBMCs of SLE patients attenuates type I interferon pathway activation by increasing miR-146a expression. Our work provides a strategy to define non-coding RNA functional regulatory elements using disease-associated variants and provides mechanistic links between autoimmune disease risk genetic variation and disease etiology.

Date: 2021
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DOI: 10.1038/s41467-020-20460-1

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