Bromodomains—Placing BETs on Chromatin in Heart Failure?

The past several decades have seen a steep rise in the numbers of patients with chronic heart failure, as patients now tend to survive primary cardiac insults such as heart attacks. The natural history of heart failure is ominous, with progressive deterioration of heart function leading to mortality rates of 50% at 5 years. Therapies that abrogate the accompanying stress hormone activation in this disease improve long-term outcomes, but the field has been stagnant for two decades: Pharmacologic approaches aimed at directly strengthening the contractile function of the heart have generally failed. Under conditions of pressure overload or excessive hormonal stimulation, heart muscle cells—or cardiomyocytes—alter their gene expression profile in a maladaptive fashion, further hastening a heart failure progression. However, the precise mechanisms linking wholesale changes in gene transcription to heart failure pathogenesis are incompletely understood. Recent work in epigenetics and cancer biology has highlighted the importance of bromodomain proteins, which bind and recognize DNA marked by histone acetylation. One important family of these so-called “epigenetic readers” is the BET (Bromodomain and Extra Terminal) family of acetyl-lysine recognition proteins. Recent studies have shown that BETs regulate chromatin-based signaling across the genome and function as key switches for gene transcription. The study of BET function in vivo has recently been accelerated by the development of a first-in-class, potent, and selective small-molecule BET-inhibitor, termed JQ1, by the Bradner laboratory. This prototype drug has been shown to have robust antitumor effects toward a variety of malignancies. It is against this backdrop that Haldar, Bradner, and colleagues report their findings implicating BET proteins as previously unidentified regulators of heart failure pathogenesis. The authors first sought to determine whether pathologic cardiomyocyte hypertrophy—modeled in vitro by using neonatal rat ventricular myocytes (NRVM)—could be abrogated with BET inhibition. When incubated with either BET-specific small interfering RNA or the JQ1 inhibitor, NRVM were protected against pathologic cellular hypertrophy. A transcriptional analysis of these cultured cardiomyocytes demonstrated that a large number of transcripts induced in this model were in fact dependent on BET activation. Next, the authors tested the effect of BET inhibition in vivo using two mouse models of heart failure, chronic pressure overload, and excessive neurohormonal stimulation. Remarkably, BET-inhibition led to near-normalization of anatomic, echocardiographic, and histopathologic parameters of the heart failure phenotype despite continuous exposure to stress. Elegant genome-wide transcriptional analysis of these mouse hearts defined the specific transcriptional networks controlled by BETs. Furthermore, these mechanistic studies revealed that BETs populate active cardiac enhancers and promoters genome-wide and that BET inhibition abrogates the ability of locally hyperacetylated regions of chromatin to signal downstream to RNA polymerase II and induce pathological genes. Parallel analysis of hearts from human patients with heart failure confirmed that these BET-regulated gene programs are also dysregulated in human disease. This paper suggests that epigenetic readers such as BET family proteins are crucial mediators of the genetic reprogramming that is both cause and consequence of heart failure in experimental models. The interaction of BETs with their chromatin substrates has now been shown to be amenable to inhibition by small molecules, with drug development programs already established for cancer. Thus, this study establishes an important proof-of-concept with exciting implications for novel therapeutic approaches targeting epigenetic reader proteins and chromatin-dependent signal transduction in the diseased heart. P. Anand et al ., BET bromodomains mediate transcriptional pause release in heart failure. Cell 154 , 569–582 (2013). [[Abstract]][1] [1]: http://www.cell.com/abstract/S0092-8674(13)00884-2