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: Jie Yin, Jianmei W Leavenworth, Yang Li, Qi Luo, Huafeng Xie, Xinhua Liu, Shan Huang, Han Yan, Zheng Fu, Liyun Y Zhang, Litao Zhang, Junwei Hao, Xudong Wu, Xianming Deng, Charles W M Roberts, Stuart H Orkin, Harvey Cantor, Xi Wang
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 52 Pg. 15988-93 (Dec 29 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 26668377 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-2 Receptor beta Subunit
• NK Cell Lectin-Like Receptor Subfamily K
• Histone Methyltransferases
• Enhancer of Zeste Homolog 2 Protein
• Ezh2 protein, mouse
• Histone-Lysine N-Methyltransferase
• Polycomb Repressive Complex 2

Topics

• Animals
• Cell Differentiation (genetics)
• Cell Line, Tumor
• Cell Lineage (genetics)
• Cell Proliferation (genetics)
• Cell Survival (genetics)
• Cells, Cultured
• Enhancer of Zeste Homolog 2 Protein
• Flow Cytometry
• Gene Expression Profiling
• Hematopoietic Stem Cells (metabolism)
• Histone Methyltransferases
• Histone-Lysine N-Methyltransferase (genetics, metabolism)
• Humans
• Immunoblotting
• Interleukin-2 Receptor beta Subunit (genetics, metabolism)
• K562 Cells
• Killer Cells, Natural (metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• NK Cell Lectin-Like Receptor Subfamily K (genetics, metabolism)
• Polycomb Repressive Complex 2 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction