(Press-News.org) PHILADELPHIA— Historically, scientists have studied how cells develop and give rise to specialized cells, such as heart, liver, or skin cells, by examining specific proteins. However, it remains unclear how many of these proteins influence the activity of hundreds of genes at the same time to turn one cell type into another cell type. For example, as the heart develops, stem cells and other specialized cells will give rise to heart muscle cells, endothelial cells (lining of blood vessels), smooth muscle cells, and cardiac fibroblasts. But the details of this process remain mysterious.
As a result of a $6 million, seven-year grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH), researchers from the Perelman School of Medicine at the University of Pennsylvania are launching new efforts to uncover how the development and maintenance of heart cells is influenced by DNA. These insights could help drive future research on new therapies for cardiac disease.
Penn Medicine researchers propose that nuclear architecture, which governs the availability of hundreds of genes within a cell, plays a critical role in achieving the proper identity of a cell. Specifically, they plan to study how the packaging and organization of DNA in 3D—meaning understanding how DNA folds and twists in a complex way to fit into the tiny space of a cell nucleus—impacts cell development. The work is supported by their previous research, which shows that nuclear architecture governs cardiac cellular identity during both development and disease.
“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.”
The way the nucleus is organized inside cells plays a crucial role in controlling the genes that determine cell identity. The nucleus acts like the command center of the cell, controlling what genes are accessible or available for use.
The Jain lab’s work suggests that the way the DNA is folded and arranged within the nucleus can determine which genes are accessible and active, influencing the cell's identity. The way the DNA is folded and organized can be compared to a complex origami structure, where each fold and crease determines the final shape and function. The research aims to unravel the role of genome folding in controlling cell behavior, particularly in heart cells, and to identify key processes involved in this regulation. Researchers will also explore how the spatial positioning of DNA affects gene activity during the development of heart cells. By studying this process, researchers can examine how the identity of heart cells is maintained. This process is important for our overall health; incorrect development of heart cells or altering its identity could 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.”
This research is supported by the National Heart, Lung, and Blood Institute of the NIH (R35HL166663).
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Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $9.9 billion enterprise.
The Perelman School of Medicine is consistently among the nation's top recipients of funding from the National Institutes of Health, with $546 million awarded in the 2021 fiscal year.
The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.
Penn Medicine is powered by a talented and dedicated workforce of more than 47,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2021, Penn Medicine provided more than $619 million to benefit our community.
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