Nsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis

Wen-Lan Yang; Weinan Qiu; Ting Zhang; Kai Xu; Zi-Juan Gu; Yu Zhou; Heng-Ji Xu; Zhong-Zhou Yang; Bin Shen; Yong-Liang Zhao; Qi Zhou; Ying Yang; Wei Li; Peng-Yuan Yang; Yun-Gui Yang

doi:10.1038/s41467-023-36595-w

Nsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis

Nat Commun. 2023 Feb 16;14(1):863. doi: 10.1038/s41467-023-36595-w.

Authors

Wen-Lan Yang^#^{1

2}, Weinan Qiu^#^{1

3

4}, Ting Zhang^#^{1

5}, Kai Xu^#^{6

7

8}, Zi-Juan Gu^#^{3

9}, Yu Zhou¹⁰, Heng-Ji Xu^{1

11}, Zhong-Zhou Yang¹², Bin Shen¹⁰, Yong-Liang Zhao^{1

11}, Qi Zhou^{6

7

8}, Ying Yang^{13

14

15}, Wei Li^{16

17

18}, Peng-Yuan Yang¹⁹, Yun-Gui Yang^{20

21

22}

Affiliations

¹ Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
² Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China.
³ Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China.
⁴ Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
⁵ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China.
⁶ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
⁷ Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
⁸ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
⁹ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, 100101, China.
¹⁰ State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China.
¹¹ University of Chinese Academy of Sciences, Beijing, 100049, China.
¹² State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Nanjing University Medical School, 210093, Nanjing, China.
¹³ Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China. yingyang@big.ac.cn.
¹⁴ Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China. yingyang@big.ac.cn.
¹⁵ Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. yingyang@big.ac.cn.
¹⁶ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. liwei@ioz.ac.cn.
¹⁷ Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. liwei@ioz.ac.cn.
¹⁸ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China. liwei@ioz.ac.cn.
¹⁹ Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China. pyyang@ibp.ac.cn.
²⁰ Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China. ygyang@big.ac.cn.
²¹ Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China. ygyang@big.ac.cn.
²² Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. ygyang@big.ac.cn.

^# Contributed equally.

Abstract

T helper 17 (Th17) cells are a subset of CD4⁺ T helper cells involved in the inflammatory response in autoimmunity. Th17 cells secrete Th17 specific cytokines, such as IL-17A and IL17-F, which are governed by the master transcription factor RoRγt. However, the epigenetic mechanism regulating Th17 cell function is still not fully understood. Here, we reveal that deletion of RNA 5-methylcytosine (m⁵C) methyltransferase Nsun2 in mouse CD4⁺ T cells specifically inhibits Th17 cell differentiation and alleviates Th17 cell-induced colitis pathogenesis. Mechanistically, RoRγt can recruit Nsun2 to chromatin regions of their targets, including Il17a and Il17f, leading to the transcription-coupled m⁵C formation and consequently enhanced mRNA stability. Our study demonstrates a m⁵C mediated cell intrinsic function in Th17 cells and suggests Nsun2 as a potential therapeutic target for autoimmune disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / genetics
Colitis* / genetics
Gene Expression Regulation
Mice
Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
Th17 Cells*
Transcription Factors / genetics

Substances

Nuclear Receptor Subfamily 1, Group F, Member 3
Transcription Factors
Misu protein, mouse