title: MRTF-A mediates LPS-induced pro-inflammatory transcription by interacting with the COMPASS complex.
abstract: Chronic inflammation underscores the pathogenesis of a range of human diseases. Lipopolysaccharide (LPS) elicits strong pro-inflammatory responses in macrophages through the transcription factor NF-κB. The epigenetic mechanism underlying LPS-induced pro-inflammatory transcription is not fully understood. Herein, we describe a role for myocardin-related transcription factor A (MRTF-A, also known as MKL1) in this process. MRTF-A overexpression enhanced NF-κB-dependent pro-inflammatory transcription, whereas MRTF-A silencing inhibited this process. MRTF-A deficiency also reduced the synthesis of pro-inflammatory mediators in a mouse model of colitis. LPS promoted the recruitment of MRTF-A to the promoters of pro-inflammatory genes in an NF-κB-dependent manner. Reciprocally, MRTF-A influenced the nuclear enrichment and target binding of NF-κB. Mechanistically, MRTF-A was necessary for the accumulation of active histone modifications on NF-κB target promoters by communicating with the histone H3K4 methyltransferase complex (COMPASS). Silencing of individual members of COMPASS, including ASH2, WDR5 and SET1 (also known as SETD1A), downregulated the production of pro-inflammatory mediators and impaired the NF-κB kinetics. In summary, our work has uncovered a previously unknown function for MRTF-A and provided insights into the rationalized development of anti-inflammatory therapeutic strategies.
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Yu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Weng
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Dai
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, Jiangsu 210029, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Fang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China feifangnjmu@yahoo.com yxu2005@gmail.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Fang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China feifangnjmu@yahoo.com yxu2005@gmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism; D057890:Epigenomics; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C431575:MRTFA protein, human; C511173:Mrtfa protein, mouse; D016328:NF-kappa B; D015534:Trans-Activators; D011495:Histone-Lysine N-Methyltransferase
keywords: COMPASS; Epigenetics; MRTF-A; NF-κB; Pro-inflammatory transcription