Cardiovascular 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.
Nucleic Acids Res. 2013 Sep;41(16):7656-72. doi: 10.1093/nar/gkt500. Epub 2013 Jun 26.
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.
钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）在病理性心肌肥厚中起着核心作用，但它调节核内基因活性以介导肥厚信号的机制仍不清楚。在这里，我们报告细胞核 CaMKII 通过直接与染色质结合并调节组蛋白 H3 丝氨酸-10 的磷酸化来激活心脏转录。这些特定的活性在体外和原代新生大鼠心肌细胞中均得到证实。肥大激动剂激活 CaMKII 信号会增加原代心脏细胞中 H3 的磷酸化，并伴有细胞肥大。相反，使用 RNA 干扰特异性沉默核 CaMKII 会降低 H3 磷酸化和细胞肥大。与心肌肥厚过程中重新激活的特定基因座相关的 CaMKII 与染色质结合增加的 H3 高磷酸化。重要的是，H3 Ser-10 磷酸化和 CaMKII 募集与染色质可及性增加相关，是染色质介导的 Mef2 转录因子转录所必需的。与其他激酶调节细胞增殖和即时早期基因激活的 H3 磷酸化不同，CaMKII 介导的 H3 信号与肥厚生长有关。这些观察结果揭示了 CaMKII 作为一种激酶向组蛋白 H3 发出信号并重塑染色质的先前未被认识的功能。它们提出了一种新的表观遗传机制来控制心肌肥厚。
