Ezh2 programs TFH differentiation by integrating phosphorylation-dependent activation of Bcl6 and polycomb-dependent repression of p19Arf. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Li, Fengyin; Zeng, Zhouhao; Xing, Shaojun; Gullicksrud, Jodi; Shan, Qiang; Choi, Jinyong; Badovinac, Vladimir; Crotty, Shane; Peng, Weiqun; Xue, Hai-Hui
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 18
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-07853-z
• Languages: English
• ISSNs: 2041-1723

Abstract

Abstract Ezh2 is an histone methyltransferase (HMT) that catalyzes H3K27me3 and functions in TH 1, TH 2, and Treg cells primarily via HMT activity. Here we show that Ezh2 ablation impairs T follicular helper (TFH ) cell differentiation and activation of the TFH transcription program. In TFH cells, most Ezh2-occupied genomic sites, including theBcl6 promoter, are associated with H3K27ac rather than H3K27me3. Mechanistically, Ezh2 is recruited by Tcf1 to directly activateBcl6 transcription, with this function requiring Ezh2 phosphorylation at Ser21. Meanwhile, Ezh2 deploys H3K27me3 to repressCdkn2a expression in TFH cells, where aberrantly upregulated p19Arf, aCdkn2a protein product, triggers TFH cell apoptosis and antagonizes Bcl6 function via protein-protein interaction. Either forced expression of Bcl6 or genetic ablation of p19Arf in Ezh2-deficient cells improves TFH cell differentiation and helper function. Thus, Ezh2 orchestrates TFH -lineage specification and function maturation by integrating phosphorylation-dependent transcriptional activation and HMT-dependent gene repression. Ezh2 is an histone methyltransferase that catalyzes H3K27me3. Here the authors show that Ezh2 promotes T follicular helper (TFH ) differentiation and helper activity, by cooperating with Tcf1 to activate Bcl6 transcription and epigenetically repressing p19Arf, an antagonist of Bcl6 function and TFH cell survival.