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

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 (A...

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Bibliographic Details
Published in:Cells (Basel, Switzerland) Switzerland), 2022-02, Vol.11 (4), p.604
Main Authors: Robinson, Emma L, Drawnel, Faye M, Mehdi, Saher, Archer, Caroline R, Liu, Wei, Okkenhaug, Hanneke, Alkass, Kanar, Aronsen, Jan Magnus, Nagaraju, Chandan K, Sjaastad, Ivar, Sipido, Karin R, Bergmann, Olaf, Arthur, J Simon C, Wang, Xin, Roderick, H Llewelyn
Format: Article
Language:English
Subjects:
Activator protein 1
Animal models
Animals
BRG1 protein
Cardiac function
Cardiomegaly - genetics
cardiomyocyte
Cardiomyocytes
Chromatin Assembly and Disassembly
Chromatin remodeling
Congestive heart failure
Experiments
Gene Expression
Genes
Histone H3
Histones
Histones - metabolism
Humans
Hypertrophy
immediate early genes
Kinases
MAP kinase
Medicin och hälsovetenskap
MSK
phosphorylated histone 3 serine 28
Phosphorylation
Proteins
Serine - metabolism
Signal transduction
Transcription factors
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Summary: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.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells11040604