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 myocytespecific 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.

Identification of a regulatory domain controlling the Nppa-Nppb gene cluster during heart development and stress

“…Such modifications have been associated with the development of cardiomyopathies in the adult heart (Mahmoud and Poizat, 2013). Demethylation of H3K9 at the promoter regions of NPPA and NPPB was associated with activation of their expression in failing human left ventricular myocardium, whereas H3K9ac was not changed and H3K27ac was modestly increased (Hohl et al, 2013), in accordance with our observations (Fig. 3B, red and green bars).…”

The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy

“…Together, our data reinforce the notion that acquisition of H3K9 methylation is key to cells achieving their differentiated state. Although changes in epigenetic marks have been reported at specific loci and, in a few cases, genome wide (37,38), we demonstrate a direct correlation in CMs between the epigenome and the transcriptome that underlies stimulus-specific pathological hypertrophy induction. Indeed, the overlaying of nascent RNA abundance and its changes during AB with alterations in the epigenome allowed us to determine an immediate correlation between the epigenome and active transcription at the time point analyzed, undiluted by posttranscriptional processes.…”

Eating disorder predisposition is associated with ESRRA and HDAC4 mutations

“…Also, ESRRA activity is repressed by nuclear receptor corepressor 1 (NCOR1), which forms a functional complex with HDAC4 (18,19). Finally, ESRRA and HDAC4 activity have both been implicated in several common physiologic processes, including the conversion of glycolytic to oxidative muscle fibers (11,18), bone formation (20,21), and cardiac function (22,23). Given our findings, we hypothesized that ESRRA and HDAC4 may also function in a common biological pathway related to the development of EDs.…”