MRTF-A mediates LPS-induced pro-inflammatory transcription by interacting with the COMPASS complex

Liming Yu, Xinyu Weng, Peng Liang, Xin Dai, Xiaoyan Wu, Huihui Xu, Mingming Fang, Fei Fang, Yong Xu

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Chronic inflammation underscores the pathogenesis of a range of human diseases. Lipopolysaccharide (LPS) elicits strong proinflammatory 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 proinflammatory 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.

Original languageEnglish (US)
Pages (from-to)4645-4657
Number of pages13
JournalJournal of cell science
Volume127
Issue number21
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2014. Published by The Company of Biologists Ltd.

Keywords

  • COMPASS
  • Epigenetics
  • MRTF-A
  • NF-κB
  • Pro-inflammatory transcription

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