Setd2 supports GATA3+ST2+ thymic-derived Treg cells and suppresses intestinal inflammation

Zhaoyun Ding, Ting Cai, Jupei Tang, Hanxiao Sun, Xinyi Qi, Yunpeng Zhang, Yan Ji, Liyun Yuan, Huidan Chang, Yanhui Ma, Hong Zhou, Li Li (), Huiming Sheng () and Ju Qiu ()
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Zhaoyun Ding: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Ting Cai: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Jupei Tang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Hanxiao Sun: Shanghai Jiao Tong University School of Medicine
Xinyi Qi: Shanghai Jiao Tong University School of Medicine (SJTUSM)
Yunpeng Zhang: Shanghai Jiao Tong University School of Medicine
Yan Ji: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Liyun Yuan: University of Chinese Academy of Sciences, Chinese Academy of Science
Huidan Chang: University of Chinese Academy of Sciences, Chinese Academy of Science
Yanhui Ma: Shanghai Jiao Tong University School of Medicine
Hong Zhou: Anhui Medical University
Li Li: Shanghai Jiao Tong University
Huiming Sheng: Shanghai Jiao Tong University School of Medicine
Ju Qiu: University of Chinese Academy of Sciences, Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Treg cells acquire distinct transcriptional properties to suppress specific inflammatory responses. Transcription characteristics of Treg cells are regulated by epigenetic modifications, the mechanism of which remains obscure. Here, we report that Setd2, a histone H3K36 methyltransferase, is important for the survival and suppressive function of Treg cells, especially those from the intestine. Setd2 supports GATA3+ST2+ intestinal thymic-derived Treg (tTreg) cells by facilitating the expression and reciprocal relationship of GATA3 and ST2 in tTreg cells. IL-33 preferentially boosts Th2 cells rather than GATA3+ Treg cells in Foxp3Cre-YFPSetd2 flox/flox mice, corroborating the constraint of Th2 responses by Setd2 expression in Treg cells. SETD2 sustains GATA3 expression in human Treg cells, and SETD2 expression is increased in Treg cells from human colorectal cancer tissues. Epigenetically, Setd2 regulates the transcription of target genes (including Il1rl1) by modulating the activity of promoters and intragenic enhancers where H3K36me3 is typically deposited. Our findings provide mechanistic insights into the regulation of Treg cells and intestinal immunity by Setd2.

Date: 2022
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DOI: 10.1038/s41467-022-35250-0

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