| Literature DB >> 26668377 |
Jie Yin1, Jianmei W Leavenworth2, Yang Li1, Qi Luo3, Huafeng Xie4, Xinhua Liu5, Shan Huang1, Han Yan1, Zheng Fu6, Liyun Y Zhang7, Litao Zhang8, Junwei Hao9, Xudong Wu10, Xianming Deng11, Charles W M Roberts12, Stuart H Orkin13, Harvey Cantor2, Xi Wang14.
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.Entities:
Keywords: NKG2D; epigenetic regulation; hematopoietic stem and progenitor cells; histone modification; innate immunity
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Year: 2015 PMID： 26668377 PMCID： PMC4702963 DOI： 10.1073/pnas.1521740112
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205