MSK-Mediated Phosphorylation of Histone H3 Ser28 Couples MAPK Signalling with Early Gene Induction and Cardiac Hypertrophy.

Emma L Robinson,Saher Mehdi,Hanneke Okkenhaug,Caroline R Archer,Chandan K Nagaraju,Olaf Bergmann,Wei Liu,H Llewelyn Roderick,J Simon C Arthur,Karin R Sipido,Ivar Sjaastad,Faye M Drawnel,Jan Magnus Aronsen,Xin Wang,Kanar Alkass

doi:10.3390/cells11040604

Abstract

Heart failure is a leading cause of death that develops subsequent to deleterious hypertrophic cardiac remodelling. MAPK pathways play a key role in coordinating the induction of gene expression during hypertrophy. Induction of the immediate early gene (IEG) response including activator protein 1 (AP-1) complex factors is a necessary and early event in this process. How MAPK and IEG expression are coupled during cardiac hypertrophy is not resolved. Here, in vitro, in rodent models and in human samples, we demonstrate that MAPK-stimulated IEG induction depends on the mitogen and stress-activated protein kinase (MSK) and its phosphorylation of histone H3 at serine 28 (pH3S28). pH3S28 in IEG promoters in turn recruits Brg1, a BAF60 ATP-dependent chromatin remodelling complex component, initiating gene expression. Without MSK activity and IEG induction, the hypertrophic response is suppressed. These studies provide new mechanistic insights into the role of MAPK pathways in signalling to the epigenome and regulation of gene expression during cardiac hypertrophy.

Highlights

Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity worldwide [1]
Here for additional immediate early gene (IEG) (Figure S1A). The relevance of this model is supported by the hypertrophic response observed when cultured Neonatal Rat Ventricular Cardiomyocytes (NRVMs) are harvested after 24 h exposure to ET-1 rather than the time points used for histone phosphorylation analysis
The ET-1-stimulated increase in phosphorylation of histone H3 at serine 28 (pH3S28) was sensitive to inhibition of extracellular regulated kinases 1 and 2 (ERK1/2) signalling with PD184352 (PD; an inhibitor of the direct upstream kinase of ERK1/2, MEK1/2; Figure S1E) [11,50]

Summary

Introduction

Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity worldwide [1]. Preceding the induction of expression of genes associated with the hypertrophic state, hypertrophic cues such as pressure overload and exposure to neurohormonal agonists stimulate a MAPK-dependent rapid activation of an immediate early gene (IEG) response [11,12,13,14]. This IEG response is initiated through phosphorylation-dependent activation of the activator protein 1 (AP-1) transcription factor [14,15,16,17]. In vivo deletion of JunD or of c-Jun results in a loss of the initial adaptive response to hypertrophic stimuli and an exacerbation of the deleterious remodelling to pressure overload [24,25,26]

Methods

Results

Conclusion