title: A non-canonical function of Ezh2 preserves immune homeostasis.
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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia.
authors.forename: Ajithkumar
authors.initials: A
authors.lastname: Vasanthakumar
authors.affiliation: Institute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou, China.|Hudson Institute of Medical Research, Monash University, Clayton, Vic., Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Vic., Australia.
authors.forename: Dakang
authors.initials: D
authors.lastname: Xu
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia.
authors.forename: Aaron Tl
authors.initials: AT
authors.lastname: Lun
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kueh
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia.
authors.forename: Klaas Pjm
authors.initials: KP
authors.lastname: van Gisbergen
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.
authors.forename: Nadia
authors.initials: N
authors.lastname: Iannarella
authors.affiliation: Institute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou, China.|Hudson Institute of Medical Research, Monash University, Clayton, Vic., Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Vic., Australia.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Li
authors.affiliation: Hudson Institute of Medical Research, Monash University, Clayton, Vic., Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Vic., Australia.
authors.forename: Liang
authors.initials: L
authors.lastname: Yu
authors.affiliation: Hudson Institute of Medical Research, Monash University, Clayton, Vic., Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Vic., Australia.
authors.forename: Die
authors.initials: D
authors.lastname: Wang
authors.affiliation: Hudson Institute of Medical Research, Monash University, Clayton, Vic., Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Vic., Australia.
authors.forename: Bryan Rg
authors.identifier: 0000-0002-4969-1151
authors.initials: BR
authors.lastname: Williams
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia.
authors.forename: Stanley Cw
authors.initials: SC
authors.lastname: Lee
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Majewski
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Parkville, Vic., Australia.|ARC Centre of Excellence for Advanced Molecular Imaging, The University of Melbourne, Parkville, Vic., Australia.
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.|Department of Mathematics and Statistics, The University of Melbourne, Parkville, Vic., Australia.
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia.
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Herold
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia.
authors.forename: Axel
authors.initials: A
authors.lastname: Kallies
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia nutt@wehi.edu.au rallan@wehi.edu.au.|Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia.
authors.forename: Stephen L
authors.identifier: 0000-0002-0020-6637
authors.initials: SL
authors.lastname: Nutt
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia nutt@wehi.edu.au rallan@wehi.edu.au.|Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia.
authors.forename: Rhys S
authors.identifier: 0000-0003-0906-2980
authors.initials: RS
authors.lastname: Allan
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D006706:Homeostasis; D006801:Humans; D007109:Immunity / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011485:Protein Binding; D059748:Proteolysis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta; C513267:Zbtb16 protein, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: Ezh2; chromatin; lymphocyte; methylation; polycomb