MSK-mediated phosphorylation of Histone 3 Ser28 couples MAPK signaling with early gene induction and cardiac hypertrophy

Abstract

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.

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“…ET-1 is an endothelium-derived pluripotent factor that is fundamental in developing pathological hypertrophic remodeling (112). In line with this, Emma L. Robinson et al found that the mitogen and stress-activated protein kinase/Brg1/immediate early gene (MSK/Brg1/IEG) axis mediated ET-1 initiated cardiac hypertrophy (113). In addition, Brg1 and Brm could be the upstream factors of ET-1, promoting its expression in a timedependent manner (112).…”

Harnessing RKIP to Combat Heart Disease and Cancer

“…Further in vitro and mouse studies revealed that ligands of GPCRs that couple to Gs or Gq (but not Gi), such as angiotensin II, endothelin I, phenylephrine, and isoproterenol, induce pERK T188 , and that this phosphorylation site does not alter ERK activity but instead triggers the nuclear translocation of ERK. Subsequently, pERK T188 has been shown to trigger the activation of nuclear ERK targets such as Elk1, MSK, and c-myc, targets that not only promote cancer but are known to induce cardiomyocyte hypertrophy [ 60 , 61 , 62 ]. Indeed, pERK T188 is increased in human heart failure and hypertrophic mouse hearts [ 26 , 27 , 55 , 56 ].…”