UNC-CHAPEL HILL (US) —Chocolate may be critical to a happy Valentine’s Day, but a certain enzyme appears to be largely responsible for heart health all year round.
A new study, published in the journal Genes and Development, finds that lacking enough of the DOT1L enzyme puts patients at risk for some types of heart disease.
Researchers created a special line of mice lacking DOT1L, that were genetically predisposed to dilated cardiomyopathy, a condition in which the heart expands like a balloon, causing its walls to thin and its pumping ability to weaken.
About one in three cases of congestive heart failure is due to dilated cardiomyopathy, a condition that also occurs in children.
The “aha” moment came when researchers were able to prevent the mice from developing the disease by re-expressing a single downstream target gene, Dystrophin.
“We saw this phenotype in the heart and it could be attributed to anywhere between 1 and 1,000 genes. But when we just added back this one gene, the heart function was completely rescued,” says id the study’s lead author, Anh Nguyen, a graduate student in the lab of biochemist Yi Zhang, at the University of North Carolina-Chapel Hill.
“It was very surprising to us. Normally you’d think you’d have to add in a number of genes to really see that effect.”
The gene depends on the enzyme DOT1L to activate it—if DOT1L levels fall too low, Dystrophin ceases to perform its function, eventually leading to heart disease.
“We’ve identified a new function of DOT1L, which has been linked to leukemia before, but never linked to heart defects,” says Zhang, distinguished professor of biochemistry and biophysics.
Learning how the DOT1L affects Dystrophin could eventually help to improve diagnosis and treatment of patients with dilated cardiomyopathy and other conditions.
“The more we know about the protein, the better we can use it,” Zhang says.
The protein could be a target for gene therapy, for example. “If you could manipulate the function of DOT1L, then you could essentially regulate everything else downstream, including Dystrophin or other genes,” explains Nguyen.
The researchers also examined samples of human heart tissue. Patients with dilated cardiomyopathy had lower levels of DOT1L than patients with no underlying heart condition, suggesting that the protein’s role in humans is similar to its role in mice.
The findings also have potential relevance for Duchenne muscular dystrophy, which is caused by defects in Dystrophin function. About 90 percent of people with muscular dystrophy develop dilated cardiomyopathy; the study suggests low levels of DOT1L could be a common factor in both conditions.
Researchers from Harvard University contributed to the study.
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