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

Nat Commun. 2018 Dec 21;9(1):5452. doi: 10.1038/s41467-018-07853-z.


Ezh2 is an histone methyltransferase (HMT) that catalyzes H3K27me3 and functions in TH1, TH2, 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 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 TFH cells, where aberrantly upregulated p19Arf, a Cdkn2a 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Survival
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Enhancer of Zeste Homolog 2 Protein / physiology*
  • Epigenesis, Genetic
  • Gene Expression Regulation
  • Hepatocyte Nuclear Factor 1-alpha / metabolism*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phosphorylation
  • Proto-Oncogene Proteins c-bcl-6 / metabolism*
  • T-Lymphocytes, Helper-Inducer / physiology*
  • Virus Diseases / immunology


  • Bcl6 protein, mouse
  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Proto-Oncogene Proteins c-bcl-6
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse