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J. Biol. Chem. 283 (39): 26771-26781

© 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

Role of the Histone H3 Lysine 4 Methyltransferase, SET7/9, in the Regulation of NF-{kappa}B-dependent Inflammatory Genes

RELEVANCE TO DIABETES AND INFLAMMATION*

Formula

Yan Li{ddagger}§, Marpadga A. Reddy{ddagger}, Feng Miao{ddagger}, Narkunaraja Shanmugam{ddagger}, Jiing-Kuan Yee, David Hawkins||, Bing Ren||, , and Rama Natarajan{ddagger}§1

{ddagger}Gonda Diabetes Center, the §Graduate School of Biological Sciences and Division of Virology, Beckman Research Institute of City of Hope, Duarte, California 91010, and ||Ludwig Institute for Cancer Research, University of California, San Diego, California 92037

Abstract: Nuclear factor {kappa}-B (NF-{kappa}B)-regulated inflammatory genes, such as TNF-{alpha} (tumor necrosis factor-{alpha}), play key roles in the pathogenesis of inflammatory diseases, including diabetes and the metabolic syndrome. However, the nuclear chromatin mechanisms are unclear. We report here that the chromatin histone H3-lysine 4 methyltransferase, SET7/9, is a novel coactivator of NF-{kappa}B. Gene silencing of SET7/9 with small interfering RNAs in monocytes significantly inhibited TNF-{alpha}-induced inflammatory genes and histone H3-lysine 4 methylation on these promoters, as well as monocyte adhesion to endothelial or smooth muscle cells. Chromatin immunoprecipitation revealed that SET7/9 small interfering RNA could reduce TNF-{alpha}-induced recruitment of NF-{kappa}B p65 to inflammatory gene promoters. Inflammatory gene induction by ligands of the receptor for advanced glycation end products was also attenuated in SET7/9 knockdown monocytes. In addition, we also observed increased inflammatory gene expression and SET7/9 recruitment in macrophages from diabetic mice. Microarray profiling revealed that, in TNF-{alpha}-stimulated monocytes, the induction of 25% NF-{kappa}B downstream genes, including the histone H3-lysine 27 demethylase JMJD3, was attenuated by SET7/9 depletion. These results demonstrate a novel role for SET7/9 in inflammation and diabetes.

Received for publication April 11, 2008. Revision received June 26, 2008.

* This work was supported, in whole or in part, by National Institutes of Health Grants R01 DK065073 and R01 HL87864. This work was also supported by the Juvenile Diabetes Research Foundation (to R. N.) and a Predoctoral fellowship from the American Heart Association, Western States Affiliate (to Y. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


Formula

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2 and Table S1.

1 To whom correspondence should be addressed: Dept. of Diabetes, Beckman Research Institute of City of Hope, 1500 East Duarte Rd., Duarte, CA 91010. Tel.: 626-256-4673 (ext. 62289); Fax: 626-301-8136; E-mail: RNatarajan{at}coh.org.

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