期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 52, 页码 15988-15993出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1521740112
关键词
epigenetic regulation; NKG2D; hematopoietic stem and progenitor cells; histone modification; innate immunity
资金
- Ministry of Science and Technology of China [2014CB910100]
- National Natural Science Foundation of China [81171899, 81372230, 81422045, 21272195, 81322018]
- National Institutes of Health [AI048125, T32 CA070083, U01 CA105423, R01CA172152, R01CA113794]
- U01NCI Mouse Models of Cancer Consortium award
- Benacerraf Fellowship
- Claudia Adams Barr Program for Innovative Cancer Research
- Shanxi Scholarship Council of China [2012-089]
- International Cooperation Project of Shan Xi Science and Technology Department Grant [2012081049]
- Tianjin Natural Science Foundation Grant [12JCYBJC17200]
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.
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