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Using mice with genetic ablation of calcium\/calmodulin\u2010dependent protein kinase II<\/jats:styled-content> \u03b4<\/jats:italic> (CaMKII<\/jats:styled-content>\u03b4<\/jats:italic>), which are resistant to pathological cardiac stress, we show that CaMKII<\/jats:styled-content>\u03b4<\/jats:italic> regulates the phosphorylation of histone H3<\/jats:styled-content> at serine\u201010 during pressure overload hypertrophy. H3 S10<\/jats:styled-content> phosphorylation is strongly increased in the adult mouse heart in the early phase of cardiac hypertrophy and remains detectable during cardiac decompensation. This response correlates with up\u2010regulation of CaMKII<\/jats:styled-content>\u03b4<\/jats:italic> and increased expression of transcriptional drivers of pathological cardiac hypertrophy and of fetal cardiac genes. Similar changes are detected in patients with end\u2010stage heart failure, where CaMKII<\/jats:styled-content>\u03b4<\/jats:italic> specifically interacts with phospho\u2010H3<\/jats:styled-content>. Robust H3<\/jats:styled-content> phosphorylation is detected in both adult ventricular myocytes and in non\u2010cardiac cells in the stressed myocardium, and these signals are abolished in CaMKII<\/jats:styled-content>\u03b4<\/jats:italic>\u2010deficient mice after pressure overload. Mechanistically, fetal cardiac genes are activated by increased recruitment of CaMKII<\/jats:styled-content>\u03b4<\/jats:italic> and enhanced H3<\/jats:styled-content> phosphorylation at hypertrophic promoter regions, both in mice and in human failing hearts, and this response is blunted in CaMKII<\/jats:styled-content>\u03b4<\/jats:italic>\u2010deficient mice under stress. We also document that the chaperone protein 14\u20133\u20133 binds phosphorylated H3<\/jats:styled-content> in response to stress, allowing proper elongation of fetal cardiac genes by RNA<\/jats:styled-content> polymerase II<\/jats:styled-content> (RNAPII<\/jats:styled-content>), as well as elongation of transcription factors regulating cardiac hypertrophy. These processes are impaired in CaMKII<\/jats:styled-content>\u03b4<\/jats:italic>\u2010KO<\/jats:styled-content> mice after pathological stress. The findings reveal a novel in vivo<\/jats:italic> function of CaMKII<\/jats:styled-content>\u03b4<\/jats:italic> in regulating H3<\/jats:styled-content> phosphorylation and suggest a novel epigenetic mechanism by which CaMKII<\/jats:styled-content>\u03b4<\/jats:italic> controls cardiac hypertrophy. \u00a9 2014 The Authors. The Journal of Pathology<\/jats:italic> published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.4489","type":"journal-article","created":{"date-parts":[[2014,11,25]],"date-time":"2014-11-25T04:12:50Z","timestamp":1416888770000},"page":"606-618","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Control of histone H3<\/scp> phosphorylation by CaMKII<\/scp>\u03b4 in response to haemodynamic cardiac stress"],"prefix":"10.1002","volume":"235","author":[{"given":"Salma","family":"Awad","sequence":"first","affiliation":[{"name":"Cardiovascular Research Programme King Faisal Specialist Hospital and Research Centre Riyadh Kingdom of Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamar Mohamed Adib","family":"Al\u2010Haffar","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Programme King Faisal 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