Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Diabetes Mellitus, Experimental
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Gene Expression Profiling
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Gene Silencing
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Histone Methyltransferases
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Histone-Lysine N-Methyltransferase
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Histones / genetics
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Histones / metabolism
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Humans
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Inflammation / genetics
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Inflammation / metabolism
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Inflammation Mediators / metabolism*
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Jumonji Domain-Containing Histone Demethylases
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Metabolic Syndrome / genetics
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Metabolic Syndrome / metabolism
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Mice
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Monocytes / metabolism*
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Oligonucleotide Array Sequence Analysis
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Oxidoreductases, N-Demethylating / genetics
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Oxidoreductases, N-Demethylating / metabolism
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Promoter Regions, Genetic / genetics
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Protein Methyltransferases / antagonists & inhibitors
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Protein Methyltransferases / genetics
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Protein Methyltransferases / metabolism*
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RNA, Small Interfering / genetics
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Transcription Factor RelA / antagonists & inhibitors
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Transcription Factor RelA / genetics
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Transcription Factor RelA / metabolism*
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Tumor Necrosis Factor-alpha / biosynthesis*
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Tumor Necrosis Factor-alpha / genetics
Substances
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Histones
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Inflammation Mediators
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RNA, Small Interfering
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha
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Jumonji Domain-Containing Histone Demethylases
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KDM6B protein, human
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Kdm6b protein, mouse
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Oxidoreductases, N-Demethylating
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Histone Methyltransferases
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Protein Methyltransferases
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Histone-Lysine N-Methyltransferase
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SETD7 protein, human