HDAC4 controls histone methylation in response to elevated cardiac load
Open Access
- 22 February 2013
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 123 (3), 1359-1370
- https://doi.org/10.1172/JCI61084
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.Keywords
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