A non-canonical function of Ezh2 preserves immune homeostasis

Ajithkumar Vasanthakumar; Dakang Xu; Aaron Tl Lun; Andrew J. Kueh; Klaas Pjm van Gisbergen; Nadia Iannarella; Xiaofang Li; Liang Yu; Die Wang; Bryan Rg Williams; Stanley Cw Lee; Ian J. Majewski; Dale I. Godfrey; Gordon K. Smyth; Warren S. Alexander; Marco J. Herold; Axel Kallies; Stephen L. Nutt; Rhys S. Allan

doi:https://doi.org/10.15252/embr.201643237

A non-canonical function of Ezh2 preserves immune homeostasis

Ajithkumar Vasanthakumar, Dakang Xu, Aaron Tl Lun, Andrew J. Kueh, Klaas Pjm van Gisbergen, Nadia Iannarella, Xiaofang Li, Liang Yu, Die Wang, Bryan Rg Williams, Stanley Cw 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 journal › Article › Academic › peer-review

63 Citations (Scopus)

Abstract

Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histoneH3 (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 language	English
Pages (from-to)	619-631
Journal	EMBO reports
Volume	18
Issue number	4
DOIs	https://doi.org/10.15252/embr.201643237
Publication status	Published - 2017

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https://doi.org/10.15252/embr.201643237

Cite this

Vasanthakumar, A., Xu, D., Lun, A. T., Kueh, A. J., van Gisbergen, K. P., Iannarella, N., Li, X., Yu, L., Wang, D., Williams, B. R., Lee, S. C., Majewski, I. J., Godfrey, D. I., Smyth, G. K., Alexander, W. S., Herold, M. J., Kallies, A., Nutt, S. L., & 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

@article{aba0ac29c0ef42ff8550f598e29c9bd1,

title = "A non-canonical function of Ezh2 preserves immune homeostasis",

abstract = "Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histoneH3 (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",

author = "Ajithkumar Vasanthakumar and Dakang Xu and Lun, {Aaron Tl} and Kueh, {Andrew J.} and {van Gisbergen}, {Klaas Pjm} and Nadia Iannarella and Xiaofang Li and Liang Yu and Die Wang and Williams, {Bryan Rg} and Lee, {Stanley Cw} and Majewski, {Ian J.} and Godfrey, {Dale I.} and Smyth, {Gordon K.} and Alexander, {Warren S.} and Herold, {Marco J.} and Axel Kallies and Nutt, {Stephen L.} and Allan, {Rhys S.}",

year = "2017",

doi = "https://doi.org/10.15252/embr.201643237",

language = "English",

volume = "18",

pages = "619--631",

journal = "EMBO reports",

issn = "1469-221X",

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Vasanthakumar, A, Xu, D, Lun, AT, Kueh, AJ, van Gisbergen, KP, Iannarella, N, Li, X, Yu, L, Wang, D, Williams, BR, Lee, SC, 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

TY - JOUR

T1 - A non-canonical function of Ezh2 preserves immune homeostasis

AU - Vasanthakumar, Ajithkumar

AU - Xu, Dakang

AU - Lun, Aaron Tl

AU - Kueh, Andrew J.

AU - van Gisbergen, Klaas Pjm

AU - Iannarella, Nadia

AU - Li, Xiaofang

AU - Yu, Liang

AU - Wang, Die

AU - Williams, Bryan Rg

AU - Lee, Stanley Cw

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

Y1 - 2017

N2 - Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histoneH3 (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 histoneH3 (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

U2 - https://doi.org/10.15252/embr.201643237

DO - https://doi.org/10.15252/embr.201643237

M3 - Article

C2 - 28223321

SN - 1469-221X

VL - 18

SP - 619

EP - 631

JO - EMBO reports

JF - EMBO reports

IS - 4

ER -