title: MKL1 defines the H3K4Me3 landscape for NF-κB dependent inflammatory response.
abstract: 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.
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Yu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Fang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Dai
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Qi
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China. dafeifang@163.com.
authors.forename: Mingming
authors.initials: M
authors.lastname: Fang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China. yxu2005@gmail.com.|State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, China. yxu2005@gmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008745:Methylation; D051379:Mice; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D000074084:THP-1 Cells; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: D006657:Histones; D008070:Lipopolysaccharides; C431575:MRTFA protein, human; C498143:RELA protein, human; D015534:Trans-Activators; D051996:Transcription Factor RelA; D011495:Histone-Lysine N-Methyltransferase; C526068:Setd1A protein, human