SOX-5 activates a novel RORγt enhancer to facilitate experimental autoimmune encephalomyelitis by promoting Th17 cell differentiation

Yi Tian, Chao Han, Zhiyuan Wei, Hui Dong, Xiaohe Shen, Yiqiang Cui, Xiaolan Fu, Zhiqiang Tian, Shufeng Wang, Jian Zhou, Di Yang, Yi Sun, Jizhao Yuan, Bing Ni () and Yuzhang Wu ()
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Yi Tian: Institute of Immunology, PLA, Third Military Medical University (Army Medical University)
Chao Han: Institute of Immunology, PLA, Third Military Medical University (Army Medical University)
Zhiyuan Wei: Institute of Immunology, PLA, Third Military Medical University (Army Medical University)
Hui Dong: Institute of Immunology, PLA, Third Military Medical University (Army Medical University)
Xiaohe Shen: Shanxi Medical University
Yiqiang Cui: Nanjing Medical University
Xiaolan Fu: Institute of Immunology, PLA, Third Military Medical University (Army Medical University)
Zhiqiang Tian: Institute of Immunology, PLA, Third Military Medical University (Army Medical University)
Shufeng Wang: Institute of Immunology, PLA, Third Military Medical University (Army Medical University)
Jian Zhou: Institute of Immunology, PLA, Third Military Medical University (Army Medical University)
Di Yang: Institute of Immunology, PLA, Third Military Medical University (Army Medical University)
Yi Sun: The First Affiliated Hospital of Third Military Medical University (Army Medical University)
Jizhao Yuan: Institute of Immunology, PLA, Third Military Medical University (Army Medical University)
Bing Ni: Third Military Medical University (Army Medical University)
Yuzhang Wu: Institute of Immunology, PLA, Third Military Medical University (Army Medical University)

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract T helper type 17 (Th17) cells have important functions in the pathogenesis of inflammatory and autoimmune diseases. Retinoid-related orphan receptor-γt (RORγt) is necessary for Th17 cell differentiation and functions. However, the transcriptional regulation of RORγt expression, especially at the enhancer level, is still poorly understood. Here we identify a novel enhancer of RORγt gene in Th17 cells, RORCE2. RORCE2 deficiency suppresses RORγt expression and Th17 differentiation, leading to reduced severity of experimental autoimmune encephalomyelitis. Mechanistically, RORCE2 is looped to RORγt promoter through SRY-box transcription factor 5 (SOX-5) in Th17 cells, and the loss of SOX-5 binding site in RORCE abolishes RORCE2 function and affects the binding of signal transducer and activator of transcription 3 (STAT3) to the RORγt locus. Taken together, our data highlight a molecular mechanism for the regulation of Th17 differentiation and functions, which may represent a new intervening clue for Th17-related diseases.

Date: 2021
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DOI: 10.1038/s41467-020-20786-w

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