A non-canonical function of Ezh2 preserves immune homeostasis

Ajithkumar Vasanthakumar, Dakang Xu, Aaron T L Lun, Andrew J. Kueh, Klaas P J M van Gisbergen, Nadia Iannarella, Xiaofang Li, Liang Yu, Die Wang, Bryan RG Williams, Stanley C W Lee, Ian J. Majewski, Dale I Godfrey, Gordon K. Smyth, Warren S. Alexander, Marco J. Herold, Axel Kallies, Stephen L. Nutt, Rhys S. Allan

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)

Abstract

Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histone-H3 (H3K27me3) as part of the polycomb repressive complex 2 (PRC2) 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 PRC2 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.

Original languageEnglish
Pages (from-to)619-631
Number of pages13
JournalEMBO Reports
Volume18
Issue number4
DOIs
Publication statusPublished - 1 Apr 2017

Keywords

  • chromatin
  • Ezh2
  • lymphocyte
  • methylation
  • polycomb

Cite this

Vasanthakumar, A., Xu, D., Lun, A. T. L., Kueh, A. J., van Gisbergen, K. P. J. M., Iannarella, N., ... Allan, R. S. (2017). A non-canonical function of Ezh2 preserves immune homeostasis. EMBO Reports, 18(4), 619-631. https://doi.org/10.15252/embr.201643237
Vasanthakumar, Ajithkumar ; Xu, Dakang ; Lun, Aaron T L ; Kueh, Andrew J. ; van Gisbergen, Klaas P J M ; Iannarella, Nadia ; Li, Xiaofang ; Yu, Liang ; Wang, Die ; Williams, Bryan RG ; Lee, Stanley C W ; Majewski, Ian J. ; Godfrey, Dale I ; Smyth, Gordon K. ; Alexander, Warren S. ; Herold, Marco J. ; Kallies, Axel ; Nutt, Stephen L. ; Allan, Rhys S. / A non-canonical function of Ezh2 preserves immune homeostasis. In: EMBO Reports. 2017 ; Vol. 18, No. 4. pp. 619-631.
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abstract = "Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histone-H3 (H3K27me3) as part of the polycomb repressive complex 2 (PRC2) 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 PRC2 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.",
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Vasanthakumar, A, Xu, D, Lun, ATL, Kueh, AJ, van Gisbergen, KPJM, Iannarella, N, Li, X, Yu, L, Wang, D, Williams, BRG, Lee, SCW, Majewski, IJ, Godfrey, DI, Smyth, GK, Alexander, WS, Herold, MJ, Kallies, A, Nutt, SL & Allan, RS 2017, 'A non-canonical function of Ezh2 preserves immune homeostasis', EMBO Reports, vol. 18, no. 4, pp. 619-631. https://doi.org/10.15252/embr.201643237

A non-canonical function of Ezh2 preserves immune homeostasis. / Vasanthakumar, Ajithkumar; Xu, Dakang; Lun, Aaron T L; Kueh, Andrew J.; van Gisbergen, Klaas P J M; Iannarella, Nadia; Li, Xiaofang; Yu, Liang; Wang, Die; Williams, Bryan RG; Lee, Stanley C W; Majewski, Ian J.; Godfrey, Dale I; Smyth, Gordon K.; Alexander, Warren S. ; Herold, Marco J.; Kallies, Axel; Nutt, Stephen L.; Allan, Rhys S.

In: EMBO Reports, Vol. 18, No. 4, 01.04.2017, p. 619-631.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Vasanthakumar, Ajithkumar

AU - Xu, Dakang

AU - Lun, Aaron T L

AU - Kueh, Andrew J.

AU - van Gisbergen, Klaas P J M

AU - Iannarella, Nadia

AU - Li, Xiaofang

AU - Yu, Liang

AU - Wang, Die

AU - Williams, Bryan RG

AU - Lee, Stanley C W

AU - Majewski, Ian J.

AU - Godfrey, Dale I

AU - Smyth, Gordon K.

AU - Alexander, Warren S.

AU - Herold, Marco J.

AU - Kallies, Axel

AU - Nutt, Stephen L.

AU - Allan, Rhys S.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histone-H3 (H3K27me3) as part of the polycomb repressive complex 2 (PRC2) 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 PRC2 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.

AB - Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histone-H3 (H3K27me3) as part of the polycomb repressive complex 2 (PRC2) 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 PRC2 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.

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Vasanthakumar A, Xu D, Lun ATL, Kueh AJ, van Gisbergen KPJM, Iannarella N et al. A non-canonical function of Ezh2 preserves immune homeostasis. EMBO Reports. 2017 Apr 1;18(4):619-631. https://doi.org/10.15252/embr.201643237