HDAC4 controls histone methylation in response to elevated cardiac load

• Published in: The Journal of clinical investigation Vol. 123; no. 3; pp. 1359 - 1370
• Main Authors: Hohl, Mathias, Wagner, Michael, Reil, Jan-Christian, Müller, Sarah-Anne, Tauchnitz, Marcus, Zimmer, Angela M, Lehmann, Lorenz H, Thiel, Gerald, Böhm, Michael, Backs, Johannes, Maack, Christoph
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2013
• Subjects: Acetylation; Active Transport, Cell Nucleus; Animals; Atrial Natriuretic Factor - genetics; Atrial Natriuretic Factor - metabolism; Biomedical research; Blood Pressure; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Cardiomyopathy, Dilated - complications; Cardiomyopathy, Dilated - enzymology; Cardiomyopathy, Dilated - physiopathology; Case-Control Studies; Cells, Cultured; Development and progression; DNA methylation; Enzyme Induction; Epigenesis, Genetic; Epigenetics; Gene Expression; Genetic aspects; Heart failure; Heart Failure - enzymology; Heart Failure - etiology; Heart Failure - physiopathology; Heart Ventricles - metabolism; Hemodynamics; Histone Deacetylases - physiology; Histones; Histones - metabolism; Humans; In Vitro Techniques; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; Kinases; Male; Methylation; Methyltransferases - metabolism; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Myocardial Ischemia - complications; Myocardial Ischemia - enzymology; Myocardial Ischemia - physiopathology; Myocytes, Cardiac - metabolism; Natriuretic Peptide, Brain - genetics; Natriuretic Peptide, Brain - metabolism; Natriuretic peptides; Peptides; Physiological aspects; Promoter Regions, Genetic; Protein Processing, Post-Translational; Proteins; Rats; Rats, Sprague-Dawley; Repressor Proteins - metabolism; Repressor Proteins - physiology; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Transcription factors; Germany
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci61084

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.