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Nucleic Acids Res. 2013 Sep;41(16):7656-72. doi: 10.1093/nar/gkt500. Epub 2013 Jun 26.

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

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  • 1Cardiovascular Research Program, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Kingdom of Saudi Arabia, Institute for Genetic Medicine, University of Southern California 2250 Alcazar Street, Los Angeles, CA 90033, USA, Department of Biochemistry and Molecular Biology, University of Southern California 2250 Alcazar Street, Los Angeles, CA 90089, USA, Department of Pharmacology, University of California at Davis, Davis, CA 95616, USA and Department of Biology, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182, USA.


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.

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