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A non‐canonical function of Ezh2 preserves immune homeostasis
Author(s) -
Vasanthakumar Ajithkumar,
Xu Dakang,
Lun Aaron TL,
Kueh Andrew J,
Gisbergen Klaas PJM,
Iannarella Nadia,
Li Xiaofang,
Yu Liang,
Wang Die,
Williams Bryan RG,
Lee Stanley CW,
Majewski Ian J,
Godfrey Dale I,
Smyth Gordon K,
Alexander Warren S,
Herold Marco J,
Kallies Axel,
Nutt Stephen L,
Allan Rhys S
Publication year - 2017
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201643237
Subject(s) - ezh2 , immune system , chromatin , prc2 , histone , biology , microbiology and biotechnology , histone h3 , t cell , transcription factor , immunology , genetics , gene
Abstract Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histone‐H3 (H3K27me3) as part of the polycomb repressive complex 2 ( PRC 2) together with Suz12 and Eed. However, Ezh2 can also modify non‐histone substrates, although it is unclear whether this mechanism has a role during development. Here, we present evidence for a chromatin‐independent role of Ezh2 during T‐cell development and immune homeostasis. T‐cell‐specific depletion of Ezh2 induces a pronounced expansion of natural killer T ( NKT ) cells, although Ezh2‐deficient T cells maintain normal levels of H3K27me3. In contrast, removal of Suz12 or Eed destabilizes canonical PRC 2 function and ablates NKT cell development completely. We further show that Ezh2 directly methylates the NKT cell lineage defining transcription factor PLZF , leading to its ubiquitination and subsequent degradation. Sustained PLZF expression in Ezh2‐deficient mice is associated with the expansion of a subset of NKT cells that cause immune perturbation. Taken together, we have identified a chromatin‐independent function of Ezh2 that impacts on the development of the immune system.