title: 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: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg, Germany.
authors: Mathias
authors: M
authors: Hohl
authors: Michael
authors: M
authors: Wagner
authors: Jan-Christian
authors: JC
authors: Reil
authors: Sarah-Anne
authors: SA
authors: Müller
authors: Marcus
authors: M
authors: Tauchnitz
authors: Angela M
authors: AM
authors: Zimmer
authors: Lorenz H
authors: LH
authors: Lehmann
authors: Gerald
authors: G
authors: Thiel
authors: Michael
authors: M
authors: Böhm
authors: Johannes
authors: J
authors: Backs
authors: Christoph
authors: C
authors: Maack
mesh_terms: D000107:Acetylation; D021581:Active Transport, Cell Nucleus; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000201:enzymology* / Q000503:physiopathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D004790:Enzyme Induction; D044127:Epigenesis, Genetic; D015870:Gene Expression; D006333:Heart Failure / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism; D006655:Histone Deacetylases / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000150:complications / Q000201:enzymology* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D012097:Repressor Proteins; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D056484:Jumonji Domain-Containing Histone Demethylases; C407843:SUV39H1 protein, human; D008780:Methyltransferases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C400300:HDAC4 protein, human; D006655:Histone Deacetylases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases