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

J Biol Chem. 2015 Jul 3;290(27):16607-18. doi: 10.1074/jbc.M115.661777. Epub 2015 May 20.

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.

Keywords: Set9; beta cell (β-cell); histone methylation; inflammation; islet; nitric-oxide synthase; p65.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Histone-Lysine N-Methyltransferase
  • Histones / chemistry*
  • Histones / genetics
  • Histones / metabolism*
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / enzymology
  • Insulin-Secreting Cells / metabolism
  • Interferon-gamma / metabolism
  • Interleukin-1 / metabolism
  • Interleukin-1beta / metabolism
  • Islets of Langerhans / enzymology*
  • Islets of Langerhans / metabolism
  • Lysine / chemistry
  • Lysine / genetics
  • Lysine / metabolism*
  • Methylation
  • Mice
  • Mice, Knockout
  • Nitric Oxide Synthase Type II / genetics*
  • Nitric Oxide Synthase Type II / metabolism
  • Protein Methyltransferases / genetics
  • Protein Methyltransferases / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Histones
  • Interleukin-1
  • Interleukin-1beta
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Protein Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • Setd7 protein, mouse
  • Lysine