SET7/9 Enzyme Regulates Cytokine-induced Expression of Inducible Nitric-oxide Synthase through Methylation of Lysine 4 at Histone 3 in the Islet β Cell.

Set7/9 is an enzyme that methylates lysine 4 on histone 3 (H3K4) to maintain euchromatin architecture. While Set7/9 is enriched in islets and contributes to the transactivation of β cell specific genes including Ins1 and Slc2a, Set7/9 has also been reported to bind the p65 subunit of nuclear factor κB in non β cells and modify its transcriptional activity. Given that inflammation is a central component of β cell dysfunction in Type 1 and Type 2 diabetes, the aim of this study was to elucidate the role of Set7/9 in proinflammatory cytokine signaling in β cells. To induce inflammation, βTC3 insulinoma cells were treated with IL-1β, TNF-α, and IFN-γ. Cytokine treatment led to increased expression of inducible nitric oxide synthase (iNOS), which was attenuated by the diminution of Set7/9 using RNA interference. Consistent with previous reports, Set7/9 was co-immunoprecipitated with p65 and underwent cytosolic to nuclear translocation in response to cytokines. ChIP analysis demonstrated augmented H3K4 mono- and di-methylation of the proximal Nos2 promoter with cytokine exposure. Set7/9 was found to occupy this same region, while Set7/9 knockdown attenuated cytokine-induced histone methylation of the Nos2 gene. To test this relationship further, islets were isolated from Set7/9-deficient and wild-type mice and treated with IL-1β, TNF-α, IFN-γ. Cytokine-induced Nos2 expression was reduced in the islets from Set7/9 knockout mice. Together, our findings suggest that Set7/9 contributes to Nos2 transcription and pro-inflammatory cytokine signaling in the pancreatic β cell through activating histone modifications. [ABSTRACT FROM AUTHOR]