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Feb 1, 2012
Newly discovered heart disease genes raise questions about epigenetics
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People would like to believe that when they make certain life choices -- be they related to diet, climate or lifestyle -- the possible negative effects are confined to the individual making such choices. Yet, with the rise of epigenetics, the science of understanding and addressing molecular changes in cells that activate or de-activate genes, scientists are beginning to appreciate that one’s autonomous choices can lead to inheritable characteristics in future generations. Epigenetics further considers the possibility that genetic changes inherited early during development have long-term consequences.

Environmental factors are capable of altering gene expression. Those factors that manage to penetrate the germline chromatin (the area in reproductive cells that houses DNA that can be passed on to offspring) could be passed on to future generations. In order to be inherited, though, the epigenetic modifications must affect gene expression in the germline, an alteration that rarely occurs, even with genetic mutations. In light of the increased prevalence of obesity, diabetes, and autism, however, which have no clear genetic etiology in the majority of cases, scientists have ample support for an epigenetic hypothesis.

Epigenetics is of particular interest as it pertains to congenital heart disease. The incorrect activation of genes in fetal development can lead to congenital heart disease in adulthood. Researchers at the Gladstones Institutes explored the epigenetic underpinnings of this phenomenon in an article published January 22nd in Nature Genetics. The scientists began by identifying the mechanism by which fetal heart muscle develops into a healthy and fully formed heart, attributing this process to two genes: Ezh2 and Six1, which guide embryonic heart development.

At specific times during healthy heart development, Ezh2 acts as a regulator, shutting off genes that are no longer needed. While past research has focused on which genes are switched on during normal heart development, this paper investigated which genes must remain off in order to ensure proper heart growth. In lab experiments on mice, the Gladstones team removed Ezh2 from the mice at various developmental stages and monitored any ensuing genetic or physical changes, which they compared to mice whose Ezh2 genes remained intact. Results revealed that mice without Ezh2 developed normally to begin with, but over time began to show problems, particularly with the development of enlarged, weakened hearts incapable of efficiently pumping blood. An enlarged heart is indicative of cardiomyopathy (deterioration of the function of the heart muscle), which leads to sudden death, particularly in infants.

The Six1 gene, by comparison, is only activated for a brief period during heart development, after which Ezh2 shuts it off permanently. In experiments excluding Ezh2, Six1 was allowed to stay on, leading to the development of heart problems. Scientists discovered that when Six1 remains activated beyond its normal term, it boosts activity in other genes that are not meant to be activated in heart-muscle cells, such as genes that produce skeletal muscle. This improper growth also led to heart enlargement, failure, and death in the laboratory mice.

Based on these observations, researchers concluded that Ezh2-mediated repression of Six1 in differentiating cardiac cells is essential for stable gene expression and homeostasis in the postnatal heart. By the same token, epigenetic dysregulation in embryonic cells is a predisposing factor for adult heart disease.

The implications of this research are vast, especially in its ability to lead to possible treatments or therapies for congenital heart disease, which affects 1.3 million adults and children in the US. For example, dilated cardiomyopathy, a type of congenital heart disease, is caused by mutations in Eya4, a gene also regulated by Ezh2 in the heart. A better understanding of the Ezh2 and Six1 genes will thus foster treatment plans for related heart conditions.
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