Control of histone H3 phosphorylation by CaMKII. in response to haemodynamic cardiac stress

Salma Awad, Kamar Mohamed Adib Al-Haffar, Qussay Marashly, Pearl Quijada, Muhammad Kunhi, Nadya Al-Yacoub, Fallou S. Wade, Shamayel Faheem Mohammed, Fouad Al-Dayel, George Sutherland, Abdullah Assiri, Mark Sussman, Donald M Bers, Waleed Al-Habeeb, Coralie Poizat

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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. Using mice with genetic ablation of calcium/calmodulin-dependent protein kinase II δ (CaMKIIδ), which are resistant to pathological cardiac stress, we show that CaMKIIδ regulates the phosphorylation of histone H3 at serine-10 during pressure overload hypertrophy. H3 S10 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-regulation of CaMKIIδ and increased expression of transcriptional drivers of pathological cardiac hypertrophy and of fetal cardiac genes. Similar changes are detected in patients with end-stage heart failure, where CaMKIIδ specifically interacts with phospho-H3. Robust H3 phosphorylation is detected in both adult ventricular myocytes and in non-cardiac cells in the stressed myocardium, and these signals are abolished in CaMKIIδ-deficient mice after pressure overload. Mechanistically, fetal cardiac genes are activated by increased recruitment of CaMKIIδ and enhanced H3 phosphorylation at hypertrophic promoter regions, both in mice and in human failing hearts, and this response is blunted in CaMKIIδ-deficient mice under stress. We also document that the chaperone protein 14-3-3 binds phosphorylated H3 in response to stress, allowing proper elongation of fetal cardiac genes by RNA polymerase II (RNAPII), as well as elongation of transcription factors regulating cardiac hypertrophy. These processes are impaired in CaMKIIδ-KO mice after pathological stress. 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.

Original languageEnglish (US)
Pages (from-to)606-618
Number of pages13
JournalJournal of Pathology
Volume235
Issue number4
DOIs
StatePublished - Mar 1 2015

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Type 2
Histones
Hemodynamics
Phosphorylation
Cardiomegaly
Genes
Heart Failure
S 10
14-3-3 Proteins
Peptide Elongation Factors
Pressure
Calcium-Calmodulin-Dependent Protein Kinases
Ventricular Remodeling
RNA Polymerase II
Genetic Promoter Regions
Epigenomics
Muscle Cells
Serine
Hypertrophy
Myocardium

Keywords

  • 14-3-3
  • CaMKIIδ
  • Cardiac hypertrophy
  • Epigenetic
  • H3 phosphorylation
  • Transcription

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Awad, S., Al-Haffar, K. M. A., Marashly, Q., Quijada, P., Kunhi, M., Al-Yacoub, N., ... Poizat, C. (2015). Control of histone H3 phosphorylation by CaMKII. in response to haemodynamic cardiac stress. Journal of Pathology, 235(4), 606-618. https://doi.org/10.1002/path.4489

Control of histone H3 phosphorylation by CaMKII. in response to haemodynamic cardiac stress. / Awad, Salma; Al-Haffar, Kamar Mohamed Adib; Marashly, Qussay; Quijada, Pearl; Kunhi, Muhammad; Al-Yacoub, Nadya; Wade, Fallou S.; Mohammed, Shamayel Faheem; Al-Dayel, Fouad; Sutherland, George; Assiri, Abdullah; Sussman, Mark; Bers, Donald M; Al-Habeeb, Waleed; Poizat, Coralie.

In: Journal of Pathology, Vol. 235, No. 4, 01.03.2015, p. 606-618.

Research output: Contribution to journalArticle

Awad, S, Al-Haffar, KMA, Marashly, Q, Quijada, P, Kunhi, M, Al-Yacoub, N, Wade, FS, Mohammed, SF, Al-Dayel, F, Sutherland, G, Assiri, A, Sussman, M, Bers, DM, Al-Habeeb, W & Poizat, C 2015, 'Control of histone H3 phosphorylation by CaMKII. in response to haemodynamic cardiac stress', Journal of Pathology, vol. 235, no. 4, pp. 606-618. https://doi.org/10.1002/path.4489
Awad S, Al-Haffar KMA, Marashly Q, Quijada P, Kunhi M, Al-Yacoub N et al. Control of histone H3 phosphorylation by CaMKII. in response to haemodynamic cardiac stress. Journal of Pathology. 2015 Mar 1;235(4):606-618. https://doi.org/10.1002/path.4489
Awad, Salma ; Al-Haffar, Kamar Mohamed Adib ; Marashly, Qussay ; Quijada, Pearl ; Kunhi, Muhammad ; Al-Yacoub, Nadya ; Wade, Fallou S. ; Mohammed, Shamayel Faheem ; Al-Dayel, Fouad ; Sutherland, George ; Assiri, Abdullah ; Sussman, Mark ; Bers, Donald M ; Al-Habeeb, Waleed ; Poizat, Coralie. / Control of histone H3 phosphorylation by CaMKII. in response to haemodynamic cardiac stress. In: Journal of Pathology. 2015 ; Vol. 235, No. 4. pp. 606-618.
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