HDAC4 controls histone methylation in response to elevated cardiac load
Mathias Hohl, Michael Wagner, Jan-Christian Reil, Sarah-Anne Müller, Marcus Tauchnitz, Angela M. Zimmer, Lorenz H. Lehmann, Gerald Thiel, Michael Böhm, Johannes Backs, Christoph Maack
Mathias Hohl, Michael Wagner, Jan-Christian Reil, Sarah-Anne Müller, Marcus Tauchnitz, Angela M. Zimmer, Lorenz H. Lehmann, Gerald Thiel, Michael Böhm, Johannes Backs, Christoph Maack
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Research Article Cardiology

HDAC4 controls histone methylation in response to elevated cardiac load

Abstract

In patients with heart failure, reactivation of a fetal gene program, including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), is a hallmark for maladaptive remodeling of the LV. The mechanisms that regulate this reactivation are incompletely understood. Histone acetylation and methylation affect the conformation of chromatin, which in turn governs the accessibility of DNA for transcription factors. Using human LV myocardium, we found that, despite nuclear export of histone deacetylase 4 (HDAC4), upregulation of ANP and BNP in failing hearts did not require increased histone acetylation in the promoter regions of these genes. In contrast, di- and trimethylation of lysine 9 of histone 3 (H3K9) and binding of heterochromatin protein 1 (HP1) in the promoter regions of these genes were substantially reduced. In isolated working murine hearts, an acute increase of cardiac preload induced HDAC4 nuclear export, H3K9 demethylation, HP1 dissociation from the promoter region, and activation of the ANP gene. These processes were reversed in hearts with myocyte-specific deletion of Hdac4. We conclude that HDAC4 plays a central role for rapid modifications of histone methylation in response to variations in cardiac load and may represent a target for pharmacological interventions to prevent maladaptive remodeling in patients with heart failure.

Authors

Mathias Hohl, Michael Wagner, Jan-Christian Reil, Sarah-Anne Müller, Marcus Tauchnitz, Angela M. Zimmer, Lorenz H. Lehmann, Gerald Thiel, Michael Böhm, Johannes Backs, Christoph Maack

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Figure 3

H3K9 demethylation and HP1 dissociation in ANP and BNP promoter regions of failing myocardium.

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H3K9 demethylation and HP1 dissociation in ANP and BNP promoter regions ...
Representative PCR of ChIP assay experiments probing H3K9me2 and H3K9me3 (A), and cumulative analyses (B and C; nonfailing, n = 8; failing, n = 16). Representative PCR of ChIP probing for HP1 binding to the ANP (D) and BNP promoter (E), and cumulative analyses (F and G; nonfailing, n = 8; failing, n = 16). The ratio between H3K27ac and H3K9me2 in the promoter regions of ANP (H) and BNP (I) was calculated in nonfailing (n = 8) and failing (n = 16) myocardium and correlated with ANP (J) and BNP (K) gene expression. ChIP assay experiments on human nonfailing and failing myocardium were performed at the same time with identical conditions, and amplified PCR products performed with specific oligonucleotides directed against ANP, BNP, or GAPDH promoter regions were separated on the same agarose gel. *P < 0.05, **P < 0.01, ***P < 0.001 vs. GAPDH nonfailing; †P < 0.05, ‡P < 0.01, failing vs. nonfailing; §P < 0.05, §§P < 0.01 vs. GAPDH failing.