Fujimaki, KyokoOgihara, TakeshiMorris, David L.Oda, HisanobuIida, HitoshiFujitani, YoshioMirmira, Raghavendra G.Evans-Molina, CarmellaWatada, Hirotaka2017-05-102017-05-102015-07-03Fujimaki, K., Ogihara, T., Morris, D. L., Oda, H., Iida, H., Fujitani, Y., … Watada, H. (2015). 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. The Journal of Biological Chemistry, 290(27), 16607–16618. http://doi.org/10.1074/jbc.M115.6617771083-351Xhttps://hdl.handle.net/1805/12490SET7/9 is an enzyme that methylates histone 3 at lysine 4 (H3K4) to maintain euchromatin architecture. Although 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, 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 dimethylation of the proximal Nos2 promoter with cytokine exposure. SET7/9 was found to occupy this same region, whereas 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, and IFN-γ. Cytokine-induced Nos2 expression was reduced in the islets from SET7/9 knock-out mice. Together, our findings suggest that SET7/9 contributes to Nos2 transcription and proinflammatory cytokine signaling in the pancreatic β cell through activating histone modifications.en-USPublisher PolicyHistoneschemistrymetabolismIslets of LangerhansenzymologyLysineNitric Oxide Synthase Type IIgeneticsProtein MethyltransferasesArticle