Researchers have shown that when parts of a genome known as enhancers are missing, the heart works abnormally, a finding that bolsters the importance of DNA segments once considered "junk" because they do not code for specific proteins.
The team examined the role of two heart enhancers in the mouse genome, showing that the loss of either one resulted in symptoms that resemble human cardiomyopathy, a disease in which the heart muscle often becomes enlarged or rigid. In humans, the disease often leads to heart failure.
The findings appear in a study published in the journal Nature Communications.
In that same paper, the researchers provided a comprehensive genome-wide map of more than 80,000 enhancers considered relevant to human heart development and function. The two heart enhancers that they tested were the mouse equivalent of enhancers chosen from among that catalog.
"In genetic studies, the way you establish whether a gene is important is you delete it from the genome and see what happens," said author. "In many cases, there are genes that, if disabled, make it difficult for the organism to survive. For enhancers, it's less known what the consequences are if they are damaged or missing. To use a car analogy, if we took the battery out of a car, it wouldn't start. That's a critical component. A missing or damaged enhancer could be essential like a battery, or more similar to a missing passenger seat in the car. It's not as nice, but it's still possible to drive the car."
To assess the function of heart enhancers, the researchers first compiled a single road map to guide them. They used results from a technology called ChIP-seq (chromatin immunoprecipitation sequencing) to identify the likely heart enhancers in the human genome.
The researchers say this map will become an important tool as advances in genomics usher in a new era of personalized medicine.
Using the map, the researchers picked two enhancers located near genes associated with human heart disease. They then determined their equivalent enhancers on the mouse genome and disabled them in mice.
They compared the mice with the disabled enhancers with control mice that had no mutation and saw very large changes in gene expression in the test mice.
Echocardiograms used to image the hearts from the two groups of mice confirmed that the heart tissue of mice with a disabled enhancer was pumping with less power than normal, consistent with the signs of human cardiomyopathy.
"Prior to this work, no study had looked at what happens to heart function as a result of knocking out the heart enhancers in the genome," said the author. "What was surprising to me was that outwardly, the knockout mice seemed fine. If you just looked at them, you wouldn't necessarily see anything wrong."
With so many enhancers to test, the map could help scientists prioritize which ones to assess in animal studies and in disease research, the researchers said.
Loss of noncoding elements of genome results in heart abnormalities
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