Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-kappaB-dependent inflammatory genes. Relevance to diabetes and inflammation.
Nuclear factor kappa-B (NF-kappaB)-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-kappaB. 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-kappaB 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-kappaB 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.
Mesh Terms:
Animals, Cell Line, Diabetes Mellitus, Experimental, Gene Expression Profiling, Gene Silencing, Histone-Lysine N-Methyltransferase, Histones, Humans, Inflammation, Inflammation Mediators, Jumonji Domain-Containing Histone Demethylases, Metabolic Syndrome X, Mice, Monocytes, Oligonucleotide Array Sequence Analysis, Oxidoreductases, N-Demethylating, Promoter Regions, Genetic, Protein Methyltransferases, RNA, Small Interfering, Transcription Factor RelA, Tumor Necrosis Factor-alpha
Animals, Cell Line, Diabetes Mellitus, Experimental, Gene Expression Profiling, Gene Silencing, Histone-Lysine N-Methyltransferase, Histones, Humans, Inflammation, Inflammation Mediators, Jumonji Domain-Containing Histone Demethylases, Metabolic Syndrome X, Mice, Monocytes, Oligonucleotide Array Sequence Analysis, Oxidoreductases, N-Demethylating, Promoter Regions, Genetic, Protein Methyltransferases, RNA, Small Interfering, Transcription Factor RelA, Tumor Necrosis Factor-alpha
J. Biol. Chem.
Date: Sep. 26, 2008
PubMed ID: 18650421
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