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

Fengyin Li; Zhouhao Zeng; Shaojun Xing; Jodi A Gullicksrud; Qiang Shan; Jinyong Choi; Vladimir P Badovinac; Shane Crotty; Weiqun Peng; Hai-Hui Xue

doi:10.1038/s41467-018-07853-z

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

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

Fengyin Li, Zhouhao Zeng, Shaojun Xing, Jodi A Gullicksrud, Qiang Shan, Jinyong Choi, Vladimir P Badovinac, Shane Crotty, Weiqun Peng and Hai-Hui Xue

Nature communications, Vol.9(1), p.5452

12/21/2018

DOI: 10.1038/s41467-018-07853-z

PMCID: PMC6303346

PMID: 30575739

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Abstract

Ezh2 is an histone methyltransferase (HMT) that catalyzes H3K27me3 and functions in T 1, T 2, and Treg cells primarily via HMT activity. Here we show that Ezh2 ablation impairs T follicular helper (T ) cell differentiation and activation of the T transcription program. In T 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 cells, where aberrantly upregulated p19Arf, a Cdkn2a protein product, triggers T 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 cell differentiation and helper function. Thus, Ezh2 orchestrates T -lineage specification and function maturation by integrating phosphorylation-dependent transcriptional activation and HMT-dependent gene repression.

Phosphorylation

Cell Differentiation

Virus Diseases - immunology

Cell Survival

Epigenesis, Genetic

Mice, Inbred C57BL

Gene Expression Regulation

Mice, Transgenic

Hepatocyte Nuclear Factor 1-alpha - metabolism

Enhancer of Zeste Homolog 2 Protein - physiology

T-Lymphocytes, Helper-Inducer - physiology

Animals

Proto-Oncogene Proteins c-bcl-6 - metabolism

Cyclin-Dependent Kinase Inhibitor p16 - metabolism

Details

Title: Subtitle: Ezh2 programs T FH differentiation by integrating phosphorylation-dependent activation of Bcl6 and polycomb-dependent repression of p19Arf
Creators: Fengyin Li - Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA, 52242
Zhouhao Zeng - Department of Physics, The George Washington University, Washington DC, 20052, USA
Shaojun Xing - Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, Guangdong, P. R. China, 518071
Jodi A Gullicksrud - Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
Qiang Shan - Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA, 52242
Jinyong Choi - La Jolla Institute, La Jolla, CA, USA, 92037
Vladimir P Badovinac - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA, 52242
Shane Crotty - La Jolla Institute, La Jolla, CA, USA, 92037
Weiqun Peng - Department of Physics, The George Washington University, Washington DC, 20052, USA
Hai-Hui Xue - Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA, 52242. hai-hui-xue@uiowa.edu
Resource Type: Journal article
Publication Details: Nature communications, Vol.9(1), p.5452
DOI: 10.1038/s41467-018-07853-z
PMID: 30575739
PMCID: PMC6303346
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: England
Grant note: R01 AI114543 / NIAID NIH HHS R01 AI112579 / NIAID NIH HHS R01 AI121080 / NIAID NIH HHS I01 BX002903 / BLRD VA R21 AI119160 / NIAID NIH HHS R01 GM113961 / NIGMS NIH HHS S10 OD016199 / NIH HHS R01 AI139874 / NIAID NIH HHS P30 CA086862 / NCI NIH HHS R01 AI072543 / NIAID NIH HHS
Language: English
Date published: 12/21/2018
Academic Unit: Microbiology and Immunology; Pathology
Record Identifier: 9984046909602771

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