HDAC4 controls histone methylation in response to elevated cardiac load.

Area of Science:

• Molecular Biology
• Cardiovascular Research
• Epigenetics

Background:

• Heart failure is characterized by maladaptive left ventricular (LV) remodeling.
• Reactivation of fetal genes like atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) is a hallmark of this remodeling.
• The epigenetic mechanisms controlling this gene reactivation are not fully understood.

Purpose of the Study:

• To investigate the role of histone modifications in the reactivation of fetal genes during heart failure.
• To elucidate the function of histone deacetylase 4 (HDAC4) in regulating cardiac gene expression in response to mechanical load.

Main Methods:

• Analysis of human LV myocardium from heart failure patients.
• Chromatin immunoprecipitation assays to assess histone acetylation and methylation (H3K9me2/3) at ANP and BNP gene promoters.
• Studies in isolated working murine hearts to examine the effects of altered cardiac preload on HDAC4 localization and gene activation.
• Utilizing myocyte-specific Hdac4 knockout mice to confirm functional roles.

Main Results:

• Upregulation of ANP and BNP in failing human hearts did not correlate with increased histone acetylation at their promoter regions.
• Reduced di- and trimethylation of histone 3 lysine 9 (H3K9me2/3) and decreased binding of heterochromatin protein 1 (HP1) were observed at ANP/BNP promoters in failing hearts.
• In murine hearts, increased cardiac preload induced HDAC4 nuclear export, H3K9 demethylation, HP1 dissociation, and ANP gene activation.
• These effects were reversed in hearts lacking Hdac4 in myocytes.

Conclusions:

• HDAC4 plays a critical role in mediating rapid epigenetic changes, specifically histone methylation, in response to cardiac load.
• HDAC4-dependent epigenetic modifications are key regulators of fetal gene program reactivation in the heart.
• HDAC4 represents a potential therapeutic target for preventing maladaptive cardiac remodeling in heart failure.