MKL1 defines the H3K4Me3 landscape for NF-κB dependent inflammatory response

• Published in: Scientific reports Vol. 7; no. 1; p. 191
• Main Authors: Yu, Liming, Fang, Fei, Dai, Xin, Xu, Huihui, Qi, Xiaohong, Fang, Mingming, Xu, Yong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.03.2017; Nature Portfolio
• Subjects: 38/15; 38/61; 38/77; 38/89; 631/250/256/1980; 631/337/176; 631/337/572/2102; Animals; Cells, Cultured; Chromatin Immunoprecipitation; Disease Models, Animal; Epigenesis, Genetic; Gene Expression Profiling; Gene Expression Regulation; Histone-Lysine N-Methyltransferase - metabolism; Histones - metabolism; Humanities and Social Sciences; Humans; Lipopolysaccharides - administration & dosage; Macrophages, Peritoneal - cytology; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Methylation; Mice; multidisciplinary; Science; Science (multidisciplinary); Shock, Septic - chemically induced; Shock, Septic - genetics; Shock, Septic - metabolism; THP-1 Cells; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factor RelA - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-00301-w

Macrophage-dependent inflammatory response is considered a pivotal biological process that contributes to a host of diseases when aberrantly activated. The underlying epigenetic mechanism is not completely understood. We report here that MKL1 was both sufficient and necessary for p65-dependent pro-inflammatory transcriptional program in immortalized macrophages, in primary human and mouse macrophages, and in an animal model of systemic inflammation (endotoxic shock). Extensive chromatin immunoprecipitation (ChIP) profiling and ChIP-seq analyses revealed that MKL1 deficiency erased key histone modifications synonymous with transactivation on p65 target promoters. Specifically, MKL1 defined histone H3K4 trimethylation landscape for NF-κB dependent transcription. MKL1 recruited an H3K4 trimethyltransferase SET1 to the promoter regions of p65 target genes. There, our work has identified a novel modifier of p65-dependent pro-inflammatory transcription, which may serve as potential therapeutic targets in treating inflammation related diseases.