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.epigenetic regulation | NKG2D | hematopoietic stem and progenitor cells | histone modification | innate immunity

EZH2 Regulates the Developmental Timing of Effectors of the Pre–Antigen Receptor Checkpoints

“…2A). Our results differed from a prior study that reported a modest increase in NK cell number in the spleen of Vav1 cre Ezh2 fl/fl mice(37). In competitive chimeras, Ezh2 Δ/Δ bone marrow NK cells were present and splenic NK cell numbers were expanded when compared to controls, indicating that EZH2 limits NK cell expansion or survival (Fig.…”

Hedgehog Signaling Overcomes an EZH2-Dependent Epigenetic Barrier to Promote Cholangiocyte Expansion

“…EZH2: -1.2 fold, PCAF: +4.8 fold, P300: +1.9 fold). We subsequently focused on studying the role of EZH2, a key writer of the histone code that enzymatically mediates the H3K27Me3 repressive mark and, in several contexts, antagonizes cell differentiation by acting as an epigenetic barrier[37–39]. We hypothesized, that if functional under the conditions studied here, EZH2 can work as a barrier to cholangiocyte differentiation.…”

Epigenetic Control of the Tumor Microenvironment

“…One study showed that EZH2 expression is induced upon activation of rat hepatic stellate cells, and that the EZH2 inhibitor, 3-deazaneplanocin A, impairs stellate cell activation. EZH2 inhibitors have also been demonstrated to stimulate the effectiveness of natural killer cells [121]. Notably, EZH2 inhibitors can inhibit the antitumorigenic activities of T cells [101].…”