title: 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.
abstract: SET7/9 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.
authors.affiliation: From the Department of Metabolism and Endocrinology.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Fujimaki
authors.affiliation: From the Department of Metabolism and Endocrinology, take@juntendo.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ogihara
authors.affiliation: Medicine, and.
authors.forename: David L
authors.initials: DL
authors.lastname: Morris
authors.affiliation: Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka 811-1395, Japan.
authors.forename: Hisanobu
authors.initials: H
authors.lastname: Oda
authors.affiliation: From the Department of Metabolism and Endocrinology.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Iida
authors.affiliation: From the Department of Metabolism and Endocrinology, Therapeutic Innovations in Diabetes, and Japan Science and Technology Agency-Core Research for Evolutionary Science and Technology Program, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujitani
authors.affiliation: Medicine, and Departments of Biochemistry and Molecular Biology, Cellular and Integrative Physiology and the Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, and.
authors.forename: Raghavendra G
authors.initials: RG
authors.lastname: Mirmira
authors.affiliation: Medicine, and Departments of Biochemistry and Molecular Biology, Cellular and Integrative Physiology and the Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, and cevansmo@iu.edu.
authors.forename: Carmella
authors.initials: C
authors.lastname: Evans-Molina
authors.affiliation: From the Department of Metabolism and Endocrinology, Therapeutic Innovations in Diabetes, and Centers for Molecular Diabetology and.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Watada
mesh_terms: D000818:Animals; D017209:Apoptosis; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007515:Islets of Langerhans / Q000201:enzymology* / Q000378:metabolism; D008239:Lysine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D011496:Protein Methyltransferases / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D006657:Histones; D007375:Interleukin-1; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C562044:Setd7 protein, mouse; D008239:Lysine
keywords: Set9; beta cell (β-cell); histone methylation; inflammation; islet; nitric-oxide synthase; p65