Control of histone H3 phosphorylation by CaMKIIδ in response to haemodynamic cardiac stress.
Bottom Line: Heart failure is associated with the reactivation of a fetal cardiac gene programme that has become a hallmark of cardiac hypertrophy and maladaptive ventricular remodelling, yet the mechanisms that regulate this transcriptional reprogramming are not fully understood.Similar changes are detected in patients with end-stage heart failure, where CaMKIIδ specifically interacts with phospho-H3.The findings reveal a novel in vivo function of CaMKIIδ in regulating H3 phosphorylation and suggest a novel epigenetic mechanism by which CaMKIIδ controls cardiac hypertrophy.
Affiliation: Cardiovascular Research Programme, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.Show MeSH
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Mentions: To establish the functional link between H3 phosphorylation, 14–3–3 recruitment and the transcriptional reprogramming of fetal cardiac genes, we assessed 14–3–3 binding at fetal cardiac genes in CaMKIIδ wild-type and KO mice subjected to sham operation or TAC. 14–3–3 binding increased significantly at the ANP and β-MHC promoters and exonic region after stress in wild-type mice, but this effect was significantly reduced in CaMKIIδ-KO mice (Figure 6A). Phosphorylation of RNAPII at serine 2 (p-RNAPII S2) is associated with transcription elongation, which requires 14–3–3 . Therefore, we assessed p-RNAPII S2 at the promoter and exonic region of fetal cardiac genes and of GATA-4 in neonatal rat cardiomyocytes transfected with control siRNA (siCT) or siRNA against 14–3–3 (si14–3–3) after stimulation with the hypertrophic agonist phenylephrine (Figure 6B). As previously reported , 14–3–3 knockdown reduced p-RNAPII S2 (Figure 6B). p-RNAPII S2 was relatively low at the promoters of ANP, β-MHC and GATA-4 in both siCtr- and si14–3–3-transfected cells (Figure 6C). p-RNAPII S2 increased at ANP, β-MHC and GATA-4 exonic regions in cells with normal expression of 14–3–3, but not in cells with reduced 14–3–3 levels (Figure 6C). We also observed increased p-RNAPII S2 at ANP and β-MHC exonic regions, while it decreased at the promoter region of both genes in wild-type mice subjected to TAC, but not in CaMKIIδ-KO mice after TAC (Figure 6D, E). Taken together, these results suggest that 14–3–3 binding to phosphorylated H3 is important for the recruitment of RNAPII and elongation of fetal cardiac genes and GATA-4 during cardiac hypertrophy.
Affiliation: Cardiovascular Research Programme, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.