Scientists have created the most detailed map to date of single-cell gene regulation in heart failure. Published today in Science, the study integrates multiple layers of genomics data to identify new therapeutic targets for the world’s leading cause of death.
“Our goal is to use this atlas to discover targets that we can act on therapeutically,” said Neil C. Chi, MD, PhD, professor of medicine at UC San Diego School of Medicine. “Right now, one of the biggest limitations in cardiology is not the lack of tools, but the lack of targets. This kind of data changes that.”
While previous genetic studies have uncovered many genetic changes linked to heart failure, more than 85% of them were found in noncoding DNA regions, making it difficult to understand how they contribute to the condition and develop targeted therapeutics. Because of this, treatment options for heart failure remain limited.
“What makes this study unique is the ability to integrate multiple layers of genome regulation in the same cells,” said Bing Ren, PhD, professor emeritus of cellular and molecular medicine at UC San Diego School of Medicine and scientific director and CEO of the New York Genome Center. “These technologies allow us to look beyond which genes are active to understand how the genome is organized and controlled, revealing regulatory elements and interactions that were previously inaccessible.”
The researchers analyzed more than 750,000 individual heart cells from 36 participants with and without heart failure. Results revealed that heart failure is associated with major shifts in cell composition, with a reduction in the number of cardiomyocytes and an increase of fibroblasts and immune cells. In failing hearts, over 10,000 genes showed altered expression patterns and more than 50,000 DNA regions showed changes in chromatin states that altered the ability of proteins to interact with them.
Compared to other cell types, fibroblasts and cardiomyocytes showed the most extensive remodeling of their gene regulation networks. These cells also showed several distinct cell states as they progressed from healthy to diseased—in the case of fibroblasts, transforming into activated fibroblasts and myofibroblasts that contribute to scarring and fibrosis.
“These intermediate states are where the disease is actively unfolding,” said Chi. “If we can understand and target those transitions, we may be able to intervene earlier and more effectively.”
Integrating the single-cell atlas with genome-wide association data, the team showed that genetic changes are concentrated in specific regulatory regions active in certain cell types, particularly in cardiomyocytes. These findings suggest that targeting cardiomyocyte genes may be more effective than targeting genes found on other cell types when treating heart disease.
“This is a higher-order view of disease biology,” said Chi. “Instead of just asking which genes are turned on or off, we’re now understanding how their regulation is controlled across the genome—and that’s where most disease risk actually resides. By connecting genetic risk, gene regulation and cell-specific disease processes, this study provides a blueprint for precision therapies in heart failure. It opens the door to targeting the right mechanisms in the right cells at the right time.”
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