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

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.

Functional and molecular features of the calmodulin-interacting protein IQCG required for haematopoiesis in zebrafish

“…CaMKII and CaMKIV, which are downstream protein kinases of CaM, are both relevant to cell proliferation. It was reported that nuclear CaMKII can enhance histone H3 phosphorylation (a mitotic marker) 49 . cAMP-responsive element-binding protein, a transcription factor that can be activated by nuclear CaMKIV, is also critical for the proliferation of primary HSCs or myeloid leukaemia cells 50 .…”

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

“…114 With regard to epigenetic mechanisms, histone phosphorylation is also thought to be important for cardiac hypertrophy as shown by the recent demonstration that CaMKII also phosphorylates histones directly, which may contribute to changes in hypertrophic gene expression. 145 The possibility that ventricular remodeling can be mediated by cAMP/EPAC1/CaMKII-dependent chromatin modifications deserves further investigations.…”

An epigenetic perspective on the failing heart and pluripotent-derived-cardiomyocytes for cell replacement therapy

“…At the molecular level, HF is often marked by irregular calcium sensing and cycling within CMs, disrupted excitation-contraction coupling, increased hypertrophic signaling, impaired β-andrenergic responses, improper extracellular matrix-CM cross-talk, altered apoptotic, developmental, and metabolic signaling networks, and defective calcium/calmodulin-dependent kinase II (CaMKII) function, among others (Cohn et al, 2000;Zhang et al, 2002a;Backs et al, 2006;Bossuyt et al, 2008;Fan et al, 2012;Koitabashi and Kass, 2012;Awad et al, 2013;Ferrara et al, 2014). The latter, CaMKII is directly involved in activating myocyte enhancing factor 2 (MEF2) target genes through post-translational phosphorylation of HDACs, namely, HDACs 4, 5 and 9.…”

“…This often involves coordinating efforts with p300 HAT (Chang et al, 2004;Backs et al, 2006;Zhang et al, 2007;Bossuyt et al, 2008). Activation of MEF2 and other pro-hypertrophic transcription factors also occurs through CaMKII targeting of histone H3 and concomitant chromatin remodeling, of which overactivation of CaMKII is associated with hypertrophic phenotypes (Awad et al, 2013). p300 also serves as a co-activator of critical CM developmental transcription factor GATA-4 and was shown to promote ventricular remodeling after MI .…”

“…In fact, CM hypertrophy usually involves upregulation of fetal cardiac genes and decreased expression of adult cardiac genes, of which histone acetylation (Zhang et al, 2002a;Trivedi et al, 2007) and H3K9me3 (Majumdar et al, 2008) are thought to have defining influences on the reprogramming steps. Misregulation of histone modifications at central CM specific transcription factors and/or key signaling pathways involved in normal cardiac function has now been widely documented within MI/HF (Zhang et al, 2002a;Chang et al, 2004;Backs et al, 2006;Miyamoto et al, 2006;Trivedi et al, 2007;Zhang et al, 2007;Bossuyt et al, 2008;Majumdar et al, 2008;Movassagh et al, 2011;Awad et al, 2013;). With regards to DNA methylation, global methylation differences clearly exist between healthy and cardiomyopathic left ventricles, in which cardiac disease samples were hypomethylated at promoters and hypermethylated in gene bodies (Movassagh et al, 2011).…”