EZH2 restricts Tcf7 DNA methylation and promotes TFH differentiation during acute viral infection

Yuan Luo; Dan Li; Luoyingzi Xie; Shun Lei; Xiangyu Chen; Cong Wang; Dong Yao; Lin Li; Jingyi Fang; Cheng Chen; Shijie Yuan; Fei Li; Xiaorong Xie; Yan Zhang; Zhirong Li; Li Hu; Jianfang Tang; Lilin Ye; Zhengping Wei; Ran He

doi:10.3389/fimmu.2022.942465

EZH2 restricts Tcf7 DNA methylation and promotes T_FH differentiation during acute viral infection

Front Immunol. 2022 Aug 15:13:942465. doi: 10.3389/fimmu.2022.942465. eCollection 2022.

Authors

Yuan Luo^{1

2}, Dan Li³, Luoyingzi Xie², Shun Lei², Xiangyu Chen², Cong Wang⁴, Dong Yao⁵, Lin Li¹, Jingyi Fang², Cheng Chen², Shijie Yuan¹, Fei Li¹, Xiaorong Xie¹, Yan Zhang², Zhirong Li², Li Hu², Jianfang Tang², Lilin Ye², Zhengping Wei^{2

6}, Ran He¹

Affiliations

¹ Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Institute of Immunology, Third Military Medical University, Chongqing, China.
³ Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁴ Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China.
⁵ Department of Anesthesiology, Chongqing Public Health Medical Center, Chongqing, China.
⁶ Dermatology Hospital, Southern Medical University, Guangzhou, China.

Abstract

Follicular helper T (T_FH) cells provide specialized help for B cells to ensure optimal humoral immunity. The histone methyltransferase EZH2, as a chromatin repressor, secures the T_FH differentiation by promoting T_FH lineage associated gene expression during acute viral infection, including Tcf7 and Bcl6. By using conditional deletion murine system, we observed that EZH2 ablation in CD4⁺ T cells was accompanied by aberrant accumulation of DNA methyltransferases (DNMTs) DNMT1 and DNMT3B in T_FH cells. And the loss of EZH2 promoted aggravation of DNA methylation status at Tcf7 locus. Therefore, our findings suggested that EZH2 plays an important role in maintenance of hypomethylation at Tcf7 locus thus affecting T_FH differentiation during acute viral infection.

Keywords: DNA methylation; EZH2; LCMV; TFH cells; Tcf7.

MeSH terms

Animals
Cell Differentiation
DNA Methylation*
Enhancer of Zeste Homolog 2 Protein / metabolism*
Hepatocyte Nuclear Factor 1-alpha / genetics*
Histone Methyltransferases / metabolism
Mice
T-Lymphocytes, Helper-Inducer*
Virus Diseases* / immunology

Substances

Hepatocyte Nuclear Factor 1-alpha
Hnf1a protein, mouse
Histone Methyltransferases
Enhancer of Zeste Homolog 2 Protein
Ezh2 protein, mouse