Differential effects of REV-ERBα/β agonism on cardiac gene expression, metabolism, and contractile function in a mouse model of circadian disruption

Circadian clocks are composed of more than 10 interconnected transcriptional modulators, all of which have the potential to influence the cardiac transcriptome (and ultimately cardiac processes). Previous studies indicate that cardiomyocyte-specific BMAL1 knockout (CBK) mice exhibit a dysfunctional circadian clock (including decreased REV-ERBα/β expression) in the heart, associated with abnormalities in cardiac mitochondrial function, metabolism, signaling, and contractile function. Here we highlight decreased REV-ERBα/β as a mediator of glycogen synthesis, cardiomyocyte size, interstitial fibrosis, and contractile function abnormalities observed in CBK hearts.

DNA methylation reprograms cardiac metabolic gene expression in end-stage human heart failure

Heart failure (HF) is a leading cause of morbidity and mortality in the United States and worldwide. As a multifactorial syndrome with unpredictable clinical outcomes, identifying the common molecular underpinnings that drive HF pathogenesis remains a major focus of investigation. Disruption of cardiac gene expression has been shown to mediate a common final cascade of pathological hallmarks wherein the heart reactivates numerous developmental pathways. Although the central regulatory mechanisms that drive this cardiac transcriptional reprogramming remain unknown, epigenetic contributions are likely. In the current study, we examined whether the epigenome, specifically DNA methylation, is reprogrammed in HF to potentiate a pathological shift in cardiac gene expression. To accomplish this, we used paired-end whole genome bisulfite sequencing and next-generation RNA sequencing of left ventricle tissue obtained from seven patients with end-stage HF and three nonfailing donor hearts. We found that differential methylation was localized to promoter-associated cytosine-phosphate-guanine islands, which are established regulatory regions of downstream genes. Hypermethylated promoters were associated with genes involved in oxidative metabolism, whereas promoter hypomethylation enriched glycolytic pathways. Overexpression of plasmid-derived DNA methyltransferase 3A in vitro was sufficient to lower the expression of numerous oxidative metabolic genes in H9c2 rat cardiomyoblasts, further supporting the importance of epigenetic factors in the regulation of cardiac metabolism. Last, we identified binding-site competition via hypermethylation of the nuclear respiratory factor 1 (NRF1) motif, an established upstream regulator of mitochondrial biogenesis. These preliminary observations are the first to uncover an etiology-independent shift in cardiac DNA methylation that corresponds with altered metabolic gene expression in HF. NEW & NOTEWORTHY The failing heart undergoes profound metabolic changes because of alterations in cardiac gene expression, reactivating glycolytic genes and suppressing oxidative metabolic genes. In the current study, we discover that alterations to cardiac DNA methylation encode this fetal-like metabolic gene reprogramming. We also identify novel epigenetic interference of nuclear respiratory factor 1 via hypermethylation of its downstream promoter targets, further supporting a novel contribution of DNA methylation in the metabolic remodeling of heart failure.

Functional improvement and maturation of human cardiomyocytes derived from human pluripotent stem cells by barbaloin preconditioning

The development of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is a significant advancement in our ability to obtain cardiomyocytes in vitro for regenerative therapies and drug discovery. However, hPSC-CMs obtained via existing protocols usually exhibit a markedly immature phenotype, compared with adult cardiomyocytes, thereby limiting their application. Here we report that barbaloin preconditioning dramatically improves the morphology, structure-related cardiac gene expression, calcium handling, and electrophysiological properties of hPSC-CMs, which means that barbaloin may have the potential to induce the maturation of hPSC-CMs, providing a novel strategy to generate more adult-like cardiomyocytes and promoting the application of hPSC-CMs in regenerative medicine, drug development, and disease modeling.