title: Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity.
abstract: Changes of histone modification status at critical lineage-specifying gene loci in multipotent precursors can influence cell fate commitment. The contribution of these epigenetic mechanisms to natural killer (NK) cell lineage determination from common lymphoid precursors is not understood. Here we investigate the impact of histone methylation repressive marks (H3 Lys27 trimethylation; H3K27(me3)) on early NK cell differentiation. We demonstrate that selective loss of the histone-lysine N-methyltransferase Ezh2 (enhancer of zeste homolog 2) or inhibition of its enzymatic activity with small molecules unexpectedly increased generation of the IL-15 receptor (IL-15R) CD122(+) NK precursors and mature NK progeny from both mouse and human hematopoietic stem and progenitor cells. Mechanistic studies revealed that enhanced NK cell expansion and cytotoxicity against tumor cells were associated with up-regulation of CD122 and the C-type lectin receptor NKG2D. Moreover, NKG2D deficiency diminished the positive effects of Ezh2 inhibitors on NK cell commitment. Identification of the contribution of Ezh2 to NK lineage specification and function reveals an epigenetic-based mechanism that regulates NK cell development and provides insight into the clinical application of Ezh2 inhibitors in NK-based cancer immunotherapies.
authors.affiliation: Department of Cell Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Laboratory of Epigenetics in Development and Tumorigenesis, Tianjin Research Center of Basic Medical Sciences, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China;
authors.forename: Jie
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, MA 02115; Jianmei_Leavenworth@dfci.harvard.edu harvey_cantor@dfci.harvard.edu wangxi@tmu.edu.cn.
authors.forename: Jianmei W
authors.initials: JW
authors.lastname: Leavenworth
authors.affiliation: Department of Cell Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Laboratory of Epigenetics in Development and Tumorigenesis, Tianjin Research Center of Basic Medical Sciences, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China;
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cell Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Laboratory of Epigenetics in Development and Tumorigenesis, Tianjin Research Center of Basic Medical Sciences, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China; Department of Pharmacology, Tianjin Medical University, Tianjin 300070, China;
authors.forename: Qi
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115;
authors.forename: Huafeng
authors.initials: H
authors.lastname: Xie
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300070, China;
authors.forename: Xinhua
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cell Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Laboratory of Epigenetics in Development and Tumorigenesis, Tianjin Research Center of Basic Medical Sciences, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China;
authors.forename: Shan
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Cell Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Laboratory of Epigenetics in Development and Tumorigenesis, Tianjin Research Center of Basic Medical Sciences, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China;
authors.forename: Han
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Immunology, Tianjin Medical University, Tianjin 300070, China;
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Division of Rheumatology, Shanxi Da Yi Hospital, Shanxi Academy of Medical Sciences, Taiyuan, Shanxi 030032, China;
authors.forename: Liyun Y
authors.initials: LY
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin 300120, China;
authors.forename: Litao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurology and Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China;
authors.forename: Junwei
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Cell Biology, Tianjin Medical University, Tianjin 300070, China;
authors.forename: Xudong
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China;
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115; Department of Pediatrics, Harvard Medical School, Boston, MA 02115;
authors.forename: Charles W M
authors.initials: CW
authors.lastname: Roberts
authors.affiliation: Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115; Department of Pediatrics, Harvard Medical School, Boston, MA 02115; Howard Hughes Medical Institute, Boston, MA 02115.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, MA 02115; Jianmei_Leavenworth@dfci.harvard.edu harvey_cantor@dfci.harvard.edu wangxi@tmu.edu.cn.
authors.forename: Harvey
authors.initials: H
authors.lastname: Cantor
authors.affiliation: Department of Cell Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Laboratory of Epigenetics in Development and Tumorigenesis, Tianjin Research Center of Basic Medical Sciences, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China; Jianmei_Leavenworth@dfci.harvard.edu harvey_cantor@dfci.harvard.edu wangxi@tmu.edu.cn.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D000071221:Enhancer of Zeste Homolog 2 Protein; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics / Q000378:metabolism; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D053646:Interleukin-2 Receptor beta Subunit; D055655:NK Cell Lectin-Like Receptor Subfamily K; D000076983:Histone Methyltransferases; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2
keywords: NKG2D; epigenetic regulation; hematopoietic stem and progenitor cells; histone modification; innate immunity