Ezh2 programs TFH differentiation by integrating phosphorylation-dependent activation of Bcl6 and polycomb-dependent repression of p19Arf

• Published in: Nature communications Vol. 9; no. 1; pp. 1 - 18
• Main Authors: Li, Fengyin, Zeng, Zhouhao, Xing, Shaojun, Gullicksrud, Jodi A., Shan, Qiang, Choi, Jinyong, Badovinac, Vladimir P., Crotty, Shane, Peng, Weiqun, Xue, Hai-Hui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-12-2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/31; 38; 38/109; 38/15; 38/39; 42; 42/44; 631/208/176; 631/208/199; 631/250/1619/554/1898/1270; 631/250/2502; Ablation; Apoptosis; Bcl-6 protein; Cell activation; Cell differentiation; Differentiation (biology); Histone methyltransferase; Humanities and Social Sciences; Kinases; Lymphocytes T; multidisciplinary; Phosphorylation; Polycomb group proteins; Protein interaction; Proteins; Science; Science (multidisciplinary); Transcription activation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07853-z

Ezh2 is an histone methyltransferase (HMT) that catalyzes H3K27me3 and functions in T
H
1, T
H
2, and Treg cells primarily via HMT activity. Here we show that Ezh2 ablation impairs T follicular helper (T
FH
) cell differentiation and activation of the T
FH
transcription program. In T
FH
cells, most Ezh2-occupied genomic sites, including the
Bcl6
promoter, are associated with H3K27ac rather than H3K27me3. Mechanistically, Ezh2 is recruited by Tcf1 to directly activate
Bcl6
transcription, with this function requiring Ezh2 phosphorylation at Ser21. Meanwhile, Ezh2 deploys H3K27me3 to repress
Cdkn2a
expression in T
FH
cells, where aberrantly upregulated p19Arf, a
Cdkn2a
protein product, triggers T
FH
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 T
FH
cell differentiation and helper function. Thus, Ezh2 orchestrates T
FH
-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 (T
FH
) differentiation and helper activity, by cooperating with Tcf1 to activate Bcl6 transcription and epigenetically repressing p19Arf, an antagonist of Bcl6 function and T
FH
cell survival.