Image of a heart with a DNA double helix in front of it to indicate genetic heart diseases such as transthyretin amyloid cardiomyopathy.
Credit: iStock/SvetaP DNA double helix: iStock/Kagenmi

Researchers at the Perelman School of Medicine at the University of Pennsylvania have received a seven-year, $6 million grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) to discover how the development and maintenance of heart cells is influenced by DNA. The hope is that any new discoveries from the research could help inform the development of future therapies for heart disease.

Scientists have long studied how cells give rise to the specialized cells in the body that comprise the human heart, liver, skin cells, etc., by examining the role of specific proteins. What researchers haven’t been able to unravel is how the proteins influence the activity of hundreds of genes that cause the cells to differentiate. The new research intends to provide some of these answers of cardiac cell development.

According to a press release, the Penn Medicine research team proposed that the nuclear architecture which governs the availability of hundreds of genes within a cell play a critical role in governing the process of changing the cell into the proper cells. Their research plans call for taking a spatial approach to this research to better understand how the folds and twists of DNA that allow it to fit into the cell impacts cell development.

“This research has the potential to significantly advance our understanding of how cardiac cells arise and keep their identity for a lifetime,” said principal investigator Rajan Jain, MD, an assistant professor of Medicine and Cell and Developmental Biology in the Perelman School of Medicine at the University of Pennsylvania. “By viewing congenital heart disease and other cardiac diseases through the lens of how DNA is organized in the cell, many therapeutic opportunities that have remained untapped may come to light.”

Previous work from the Jain lab has suggested that the way DNA is folded and arranged within the cell’s nucleus helps determine which genes are accessible and active in influencing the cell’s identity. As the investigators described it, the way the DNA is folded and organized can be compared to an origami structure, where each fold and crease contributes to both the final shape of the DNA and ultimately its function.

The Penn researchers will focus on cardiac cell development to better understand the role of genome folding in controlling cell behavior and the processes involved in its regulation of the cell. In addition, the team will also explore how spatial positioning of DNA affects gene activity during the development of heart cells. The intent is to discover how the identity of heart cells is maintained, and how incorrect development of heart cells, or alterations in their identify may contribute to congenital heart disease or cardiomyopathy.

“As I trained, it was always assumed that therapies can’t target specific proteins in the nucleus, but that has changed over the last few years,” Jain said. “Leveraging those advancements and past work as an inspiration, I hope this research will eventually allow us to design new medicines that will directly target how DNA is organized.”

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