Targeting chromatin kinases reveals their role in inducible transcription of inflammatory genes

Abstract

The inflammatory response requires selective, rapid regulation of chromatin and induction of transcription for defense against pathogens and environmental insult, and also features abundant kinase activity. We sought to identify the connections between kinase pathway activity and regulation of chromatin through unbiased identification and genomic foot printing of prominent histone phosphorylation events. We identified histone H3 serine 28 phosphorylation (H3S28p) as the principal stimulation-dependent histone modification with enrichment at induced inflammatory genes in mouse macrophages stimulated with bacterial lipopolysaccharide (LPS). Use of chemical inhibitors and genetic rescue identified mitogen- and stress-activated protein kinases (MSK) as the primary mediators of H3S28p in macrophages. Cell-free transcription assays demonstrated that H3S28p directly promotes transcription. Further, we show that MSK can activate both signal-responsive transcription factors and the chromatin template with additive effects on transcription. Indeed, inhibition of MSK in macrophages selectively reduced transcription of stimulation-induced genes. Our results indicate MSK as a nexus of signaling inputs controlling multiple downstream regulators of inducible transcription.