Nuclear CaMKII enhances histone H3 phosphorylation and remodels chromatin during cardiac hypertrophy

Salma Awad, Muhammad Kunhi, Gillian H. Little, Yan Bai, Woojin An, Donald M Bers, Larry Kedes, Coralie Poizat

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a central role in pathological cardiac hypertrophy, but the mechanisms by which it modulates gene activity in the nucleus to mediate hypertrophic signaling remain unclear. Here, we report that nuclear CaMKII activates cardiac transcription by directly binding to chromatin and regulating the phosphorylation of histone H3 at serine-10. These specific activities are demonstrated both in vitro and in primary neonatal rat cardiomyocytes. Activation of CaMKII signaling by hypertrophic agonists increases H3 phosphorylation in primary cardiac cells and is accompanied by concomitant cellular hypertrophy. Conversely, specific silencing of nuclear CaMKII using RNA interference reduces both H3 phosphorylation and cellular hypertrophy. The hyper-phosphorylation of H3 associated with increased chromatin binding of CaMKII occurs at specific gene loci reactivated during cardiac hypertrophy. Importantly, H3 Ser-10 phosphorylation and CaMKII recruitment are associated with increased chromatin accessibility and are required for chromatin-mediated transcription of the Mef2 transcription factor. Unlike phosphorylation of H3 by other kinases, which regulates cellular proliferation and immediate early gene activation, CaMKII-mediated signaling to H3 is associated with hypertrophic growth. These observations reveal a previously unrecognized function of CaMKII as a kinase signaling to histone H3 and remodeling chromatin. They suggest a new epigenetic mechanism controlling cardiac hypertrophy.

Original languageEnglish (US)
Pages (from-to)7656-7672
Number of pages17
JournalNucleic Acids Research
Volume41
Issue number16
DOIs
StatePublished - Sep 2013

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Calcium-Calmodulin-Dependent Protein Kinase Type 2
Cardiomegaly
Histones
Chromatin
Phosphorylation
Hypertrophy
Phosphotransferases
Histamine Agonists
Calcium-Calmodulin-Dependent Protein Kinases
Immediate-Early Genes
Chromatin Assembly and Disassembly
RNA Interference
Cardiac Myocytes
Epigenomics
Serine
Transcriptional Activation
Genes
Transcription Factors
Cell Proliferation

ASJC Scopus subject areas

  • Genetics

Cite this

Nuclear CaMKII enhances histone H3 phosphorylation and remodels chromatin during cardiac hypertrophy. / Awad, Salma; Kunhi, Muhammad; Little, Gillian H.; Bai, Yan; An, Woojin; Bers, Donald M; Kedes, Larry; Poizat, Coralie.

In: Nucleic Acids Research, Vol. 41, No. 16, 09.2013, p. 7656-7672.

Research output: Contribution to journalArticle

Awad, S, Kunhi, M, Little, GH, Bai, Y, An, W, Bers, DM, Kedes, L & Poizat, C 2013, 'Nuclear CaMKII enhances histone H3 phosphorylation and remodels chromatin during cardiac hypertrophy', Nucleic Acids Research, vol. 41, no. 16, pp. 7656-7672. https://doi.org/10.1093/nar/gkt500
Awad, Salma ; Kunhi, Muhammad ; Little, Gillian H. ; Bai, Yan ; An, Woojin ; Bers, Donald M ; Kedes, Larry ; Poizat, Coralie. / Nuclear CaMKII enhances histone H3 phosphorylation and remodels chromatin during cardiac hypertrophy. In: Nucleic Acids Research. 2013 ; Vol. 41, No. 16. pp. 7656-7672.
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