MSK phosphorylation of H3S28 is required for immediate early gene induction and cardiac hypertrophy

Heart failure is a leading cause of death, developing subsequent to deleterious hypertrophic cardiac remodelling associated with pathologies including hypertension and myocardial infarction. MAPK signalling pathways, acting via transcription factors, play a key role in coordinating the induction of gene expression during hypertrophy. Induction of the immediate early gene (IEG) response, characterised by increased expression of AP-1 factors, is a necessary and early event in this process. How MAPK signalling and IEG expression are coupled during cardiac hypertrophy is not yet resolved. Here, in vitro, in rodent models and in human samples, we demonstrate that the MAPK-stimulated IEG response depends on the mitogen and stress activated protein kinase (MSK) and its phosphorylation of histone H3 at serine 28 (H3S28). Brg-1, a BAF60 ATP-dependent chromatin remodelling complex component, is recruited to IEG promoters harbouring phosphorylated H3S28, initiating their expression. In the absence of MSK activity and IEG induction, the hypertrophic response is suppressed. Together, these studies provide new mechanistic insights into hypertrophic gene regulation and highlight the role of signalling to the epigenome in cardiac hypertrophy. Brief summary one sentenceMSK1/2 phosphorylation of Histone 3 Serine 28 couples MAPK signalling with chromatin remodelling and immediate early gene expression to induce pro-hypertrophic cardiac transcriptional responses.