MKL 1 is an epigenetic mediator of TNF ‐α‐induced proinflammatory transcription in macrophages by interacting with ASH 2

Tumor necrosis factor alpha ( TNF ‐α) is a prototypical proinflammatory cytokine that can elicit strong inflammation in macrophages by activating NF ‐κB. The underlying epigenetic mechanism is obscure. We show here that megakaryocytic leukemia 1 (MKL1) is an epigenetic mediator of TNF ‐α‐induced proinflammatory transcription. Overexpression of a dominant negative form of MKL 1 abrogates TNF ‐α‐induced transactivation of proinflammatory genes. Proteomic analysis identifies the histone H3K4 trimethyltransferase ASH 2 as a potential cofactor for MKL 1. In response to TNF ‐α stimulation, ASH 2 is recruited by MKL 1 and interacts with MKL 1 to catalyze H3K4 di‐ and trimethylation. ASH 2 modulates proinflammatory transcription at least in part by altering the affinity of p65 for target promoters. Together, our data support an interplay between MKL 1 and ASH 2 to promote TNF ‐α‐induced proinflammatory transcription in macrophages.