Chromatin state dynamics during NK cell activation

Abstract

Studies of Natural Killer (NK) cell cytotoxicity have mainly focused on the balance of activating and inhibitory receptors, signaling transduction, calcium influx, formation of immune synapse, and cytolytic degranulation. However, little is known about the chromatin state of NK cells and the impact of its changes during target recognition. In this study, we investigate the contribution of chromatin state dynamics during NK cell activation by comprehensively analyzing a set of microarray data and two sets of Chromatin Immunoprecipitation-Sequencing (ChIP-seq) data. We find that the expression of several histone demethylases and methyltransferases was influenced upon stimulation. Furthermore, we notice that a series of genes, including PI3KCA, NFATC1and TNFSF9, which play important roles during NK cell activation, were at ‘poised’ state prior to activation, and that modifications of H3K4me3 and H3K27me3 on these promotors were sensitive to stimulation with Phorbol Myristate Acetate (PMA) and Ionomycin (Iono) in the NK92MI cell line. Finally, we demonstrate that a series of small molecule inhibitors, which are specific to H3K4 and H3K27 modification, enhance degranulation or the expression levels of IFN-γ and TNF-α. Our results suggest that the histone modification state has a profound impact on NK cell activation, and provide novel insights into the regulation of NK cellular cytotoxicity and immunoregulatory function by chromatin state dynamics.

Comparison of splenocyte microRNA expression profiles of pigs during acute and chronic toxoplasmosis

“…Inhibition of IL-12 production is an important part of the immune evasion mechanism of T. gondii [48]. TNFSF9 was confirmed to play important roles during NK and B cell activation [49, 50]. Therefore, the differences in the expression patterns of cytokines regulated by miRNAs that we observed at 10 and 50 DPI may be due to differences in the host immune responses induced by acute and chronic T. gondii infections.…”

Epigenetic modifiers as new immunomodulatory therapies in solid tumours

“…NK cells are typically activated and more cytotoxic in presence of IFNc, which induces trained immunity [104]. These characteristics can be enhanced by EZH2 inhibition [105,106], as well as BET inhibition that induces NK activating ligands and receptors [55]. Cytokines such as IFNc, IL4 and IL1 will determine the macrophage behaviour towards tumours cells (either protective or cytotoxic).…”

Epigenetic Modifiers: Anti-Neoplastic Drugs With Immunomodulating Potential

“…Moreover, using a combination of microarray and ChIP-sequencing analysis, Li et al found that NK cell activation of the NK-92MI cell line is characterized by dynamic changes in the expression of HDM and HMT as well as changes in H3K27me3 and H3K4me3 and specific loci. Inhibition of H3K27me3 using UNC-1999 resulted in increased degranulation capacity of NK cells ( 159 ).…”