期刊
CELLS
卷 11, 期 4, 页码 -出版社
MDPI
DOI: 10.3390/cells11040604
关键词
cardiomyocyte; MSK; phosphorylated histone 3 serine 28; immediate early genes; hypertrophy
类别
资金
- Odysseus Award
- Research Foundation Flanders (FondsWetenschappelijk Onderzoek
- FWO) [90663, G0C6419N]
- Babraham Institute
- Biotechnology and Biological Sciences Research Council (BBSRC) [BBS/E/B/0000C116, BBS/E/B/000C0402]
- Royal Society [UF041311]
- BBSRC [BBS/E/B/0000L715, BBS/E/B/0000L726]
- Wellcome Trust
- KU Leuven Faculty of Medicine
- American Heart Association Postdoctoral fellowship [829504]
- FWO [1524317N]
- Center for Regenerative Therapies Dresden
- Karolinska Institutet
- Swedish Research Council
- Ragnar Soderberg Foundation
- Ake Wiberg Foundation
- LeDucq foundation
- BBSRC [BBS/E/B/0000L726, BBS/E/B/0000L715] Funding Source: UKRI
This study demonstrates the importance of MAPK pathways in regulating gene expression during cardiac hypertrophy and provides mechanistic insights into the coupling of MAPK stimulation and IEG induction through MSK-mediated phosphorylation of histone H3, which recruits Brg1 to initiate gene expression.
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.
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