Insight & Intelligence

More »

GEN News Highlights

More »
August 10, 2018

Epigenetic Changes Implicated in Congestive Heart Failure

Source: © vishnukumar/Fotolia.com

  • Researchers at the University of Alabama at Birmingham have described an underlying mechanism that reprograms the hearts of patients with ischemic cardiomyopathy, a process that differs from patients with other forms of heart failure, collectively known as dilated (non-ischemic) cardiomyopathies. This points the way toward future personalized care for ischemic cardiomyopathy, according to the scientists.

    The team’s study (“Genome-wide DNA methylation encodes cardiac transcriptional reprogramming in human ischemic heart failure”) is published in Nature-Laboratory Investigation.

    “Ischemic cardiomyopathy (ICM) is the clinical endpoint of coronary heart disease and a leading cause of heart failure. Despite growing demands to develop personalized approaches to treat ICM, progress is limited by inadequate knowledge of its pathogenesis. Since epigenetics has been implicated in the development of other chronic diseases, the current study was designed to determine whether transcriptional and/or epigenetic changes are sufficient to distinguish ICM from other etiologies of heart failure. Specifically, we hypothesize that genome-wide DNA methylation encodes transcriptional reprogramming in ICM. RNA-sequencing analysis was performed on human ischemic left ventricular tissue obtained from patients with end-stage heart failure, which enriched known targets of the polycomb methyltransferase EZH2 compared to non-ischemic hearts. Combined RNA sequencing and genome-wide DNA methylation analysis revealed a robust gene expression pattern consistent with suppression of oxidative metabolism, induced anaerobic glycolysis, and altered cellular remodeling,” write the investigators.

    “Lastly, KLF15 was identified as a putative upstream regulator of metabolic gene expression that was itself regulated by EZH2 in a SET domain-dependent manner. Our observations, therefore, define a novel role of DNA methylation in the metabolic reprogramming of ICM. Furthermore, we identify EZH2 as an epigenetic regulator of KLF15 along with DNA hypermethylation, and we propose a novel mechanism through which coronary heart disease reprograms the expression of both intermediate enzymes and upstream regulators of cardiac metabolism such as KLF15.”

    The study used heart tissue samples collected at UAB during surgeries to implant small mechanical pumps alongside the hearts of patients with end-stage heart failure that assist in the pumping of blood. As a routine part of this procedure, a small piece of heart tissue is excised and ultimately discarded as medical waste. The current study acquired these samples from the left ventricles of five ischemic cardiomyopathy patients and six non-ischemic cardiomyopathy patients, all men between ages 49 and 70.

    The research team, led by Adam Wende, Ph.D., assistant professor in the UAB Department of Pathology, found that epigenetic changes in ischemic cardiomyopathy hearts likely reprogram the heart's metabolism and alter cellular remodeling in the heart. Epigenetics is a field that describes molecular modifications known to alter the activity of genes without changing their DNA sequence. 

    One well-established epigenetic change is the addition or removal of methyl groups to the cytosine bases of DNA. Generally, hyper-methylation is associated with a reduction of gene expression, and conversely, hypo-methylation correlates with increased gene expression. 

    Dr. Wende and colleagues found an epigenetic signature in the heart of patients with ischemic cardiomyopathy that differed from the non-ischemic hearts. Furthermore, this signature was found to reflect a long-known metabolic change in ischemic cardiomyopathy, where the heart's preference of metabolic fuel switches from using oxygen to produce energy in cells, as healthy hearts do, to an anaerobic metabolism that does not need oxygen. This anaerobic metabolic preference is seen in fetal hearts; however, after birth, the baby's heart quickly changes to oxidative metabolism.

    "Altogether, we believe that epigenetic changes encode a so-called 'metabolic plasticity' in failing hearts, the reversal of which may repair the ischemic and failing heart," Dr. Wende says.

    The researchers found that increased DNA methylation correlated with reduced expression of genes involved in oxidative metabolism. The transcription factor KLF15 is an upstream regulator of metabolic gene expression, which the researchers found is suppressed by the epigenetic regulator EZH2. Conversely, the researchers also found hypo-methylation of anaerobic glycolytic metabolic genes.

    This contribution by EZH2 offers a new molecular target for further mechanistic studies that may aid precision-based heart disease therapies, adds Dr. Wende. Of note, co-author Sooryanarayana Varambally, Ph.D., associate professor, molecular and cellular pathology, UAB, has spent over 15 years studying this protein, and has already made progress using small-molecular inhibitors to regulate EZH2 to treat various cancers.

    The Dr. Wende-led study employed a wide array of bioinformatics tools. First author Mark Pepin, M.D./Ph.D. student at UAB, used publicly available programs to create a fully automated computational pipeline, which is provided as an online supplement to the paper. This protocol, written in the R programming language, allowed the investigators to both analyze their multi-omics datasets and compare their findings to those of animal-based studies and public data repositories. "Supplying the coding scripts," Dr. Wende says, "is our way of demonstrating the rigor and reproducibility that should be expected of any bioinformatics study."

    The UAB team also performed cell culture experiments showing repression of KLF15 after EZH2 over-expression in rat cardiomyoblasts, and they demonstrated that EZH2 over-expression depended on EZH2's having an intact SET catalytic domain.

Related content

Be sure to take the GEN Poll

{{ vm.poll.Title }}

More »