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.