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; Ju Qiu

doi:10.1038/s41467-022-35250-0

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

Nat Commun. 2022 Dec 3;13(1):7468. doi: 10.1038/s41467-022-35250-0.

Authors

Zhaoyun Ding^#¹, Ting Cai^#^{1

2}, Jupei Tang¹, Hanxiao Sun³, Xinyi Qi⁴, Yunpeng Zhang⁵, Yan Ji¹, Liyun Yuan⁶, Huidan Chang⁶, Yanhui Ma⁷, Hong Zhou⁸, Li Li^{9

10}, Huiming Sheng¹¹, Ju Qiu¹²

Affiliations

¹ CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
² Medical Research Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510180, China.
³ Department of Laboratory Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China.
⁴ Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200025, China.
⁵ Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China.
⁶ CAS Key Laboratory of Computational Biology, Bio-Med Big Data Center, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Science, Shanghai, 200031, China.
⁷ Department of Laboratory Medicine, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁸ School of Life Science, Anhui Medical University, Hefei, 241000, China.
⁹ State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China. lil@sjtu.edu.cn.
¹⁰ Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China. lil@sjtu.edu.cn.
¹¹ Department of Laboratory Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China. HMSHENG@shsmu.edu.cn.
¹² CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China. qiuju@sibs.ac.cn.

^# Contributed equally.

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 Foxp3^Cre-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.

Publication types

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

MeSH terms

Animals
Colorectal Neoplasms / genetics
Colorectal Neoplasms / immunology
GATA3 Transcription Factor / genetics
GATA3 Transcription Factor / immunology
Histone Methyltransferases
Histone-Lysine N-Methyltransferase* / genetics
Histone-Lysine N-Methyltransferase* / immunology
Humans
Inflammation / genetics
Inflammation / immunology
Interleukin-1 Receptor-Like 1 Protein* / genetics
Interleukin-1 Receptor-Like 1 Protein* / immunology
Intestines* / immunology
Mice
T-Lymphocytes, Regulatory* / immunology
Thymus Gland

Substances

GATA3 protein, human
Gata3 protein, mouse
GATA3 Transcription Factor
Histone Methyltransferases
Histone-Lysine N-Methyltransferase
Il1rl1 protein, mouse
Interleukin-1 Receptor-Like 1 Protein
SETD2 protein, mouse
SETD2 protein, human
IL1RL1 protein, human