Researchers from University of California San Diego have created the most detailed map to date of how gene regulation breaks down in human heart failure, revealing how genes are controlled in specific cell types as the disease develops and pointing to potential new therapeutic targets. The study, published on July 23, 2026 in Science, integrates multiple layers of genomic data to uncover the hidden rules underlying heart failure at single-cell resolution.
"Our goal is to use this atlas to discover targets that we can act on therapeutically," said Neil 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."
Heart failure remains the leading cause of illness and death worldwide, yet treatment options remain limited, with only a small number of therapies proven to significantly improve outcomes. One major challenge has been identifying actionable biological targets. While genetic studies have uncovered many genetic changes linked to heart disease, more than 85% of these genes lie in noncoding regions of DNA — stretches that don't make proteins, but instead control when and how genes are turned on or off — making it difficult to determine how they contribute to disease.
To address this, the research team analyzed heart tissue from 36 individuals, including patients with and without heart failure. Using advanced single-cell techniques, they analyzed how genes are controlled and organized across more than 750,000 individual heart cells.
"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."
This comprehensive approach allowed the team to identify 12 major cardiac cell types and dozens of subpopulations, each with its own distinct patterns of gene control. They found that heart failure is associated with major shifts in cell composition, including increased numbers of fibroblasts — cells that produce structural support and scar tissue — and immune cells, and a reduction in cardiomyocytes — the cells responsible for contraction.
The study also revealed widespread changes in gene regulation. In cells from failing hearts, researchers identified more than 10,000 genes with altered expression and more than 50,000 regions of DNA with changed accessibility, or changes in how easily proteins can bind to DNA. These changes were particularly pronounced in cardiomyocytes and fibroblasts, which showed extensive remodeling of their regulatory networks.
Importantly, the team uncovered distinct disease-related cell states. For example, cardiomyocytes progressed from healthy to diseased through several intermediate cell states. The researchers also identified pathways through which healthy fibroblasts transform into activated fibroblasts and myofibroblasts — cell types known to contribute to fibrosis and tissue remodeling in heart failure.
"These intermediate states are where the disease is actively unfolding," Chi said. "If we can understand and target those transitions, we may be able to intervene earlier and more effectively."
The study also sheds new light on how genetic risk contributes to heart failure. By integrating their atlas with genome-wide association data, the team showed that disease-associated genetic changes are concentrated in regulatory regions active in specific cell types — particularly cardiomyocytes — and often act through long-range DNA interactions to influence gene expression. This suggests that genes in cardiomyocytes may be more viable as treatment targets for heart disease than other cardiac cell types.
In addition to offering insights into heart disease, this work helps resolve a longstanding challenge in genetics: identifying which genetic changes are truly causal and which genes they affect. By mapping these connections, the researchers provide a framework for linking genetic risk to specific biological mechanisms in heart disease.
"This is a higher-order view of disease biology," Chi said. "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."
Beyond its immediate findings, the study establishes a comprehensive resource for the scientific community. The dataset can be used to identify new drug targets, particularly in a field where therapeutic options remain limited.
"This study provides a roadmap to the landscape of major cardiac cell types of all four chambers of the normal and failing human heart," says Stavros Drakos, MD, PhD, professor of cardiovascular medicine at University of Utah Health. "These findings establish a mechanistic framework for biological pathways of heart failure development and present multiple targets for developing new therapies for heart failure."
Looking ahead, the team is already working to translate these insights into potential treatments by developing pipelines to test candidate targets identified through the analysis.
"By connecting genetic risk, gene regulation and cell-specific disease processes, this study provides a blueprint for precision therapies in heart failure," Chi said. "It opens the door to targeting the right mechanisms in the right cells at the right time."
Link to full study: Single cell multiomics and chromatin structure reveal gene regulatory dynamics in heart failure
Additional co-authors on the study include: Yang Xie, Luca Tucciarone, Elie N. Farah, Lei Chang, Qian Yang, Weston Elison, Shaina Tran, Jovina Djulamsah, Audrey Lie, Timothy Loe, Alyssa R. Holman, Sierra Corban, Justin Buchanan, Sainath Mamde, Haowen Zhou, Ruth M. Elgama, Jeffrey Huey-chuan Chiu, Rebecca Melton, Emily Griffin, Qingquan Zhang, Jacinta Lucero, Eugin Destici, Agnieszka D'Antonio-Chronowska, Allen Wang and Kyle J. Gaulton at UC San Diego; Thirupura S. Shankar, Eleni Tseliou, Vincent Huang, Sutip Navankasattusas and Craig H. Selzman at University of Utah; Zhaoning Wang at UC San Diego and Columbia University; Daofeng Li, Chanrung Seng and Ting Wang at Washington University.
The study was funded, in part, by the National Institutes of Health (Grant #NHLBI R01 HL135121, NHLBI 1R01HL166513, HG012059, NHLBI T32HL007444, and 1K08HL168315-01) and others.
The following authors declare competing interests. Consultancy fees: Drakos (Abbott), Gaulton (Genentech). Gaulton has received honoraria from Pfizer, holds stock in Neurocrine Biosciences, and his spouse is employed at Altos Labs. Drakos acknowledges research support from Novartis. Elgamal is an employee and shareholder of Pfizer. Holman is an employee of Aspen Neuroscience and holds equity in the company. Ren is a shareholder and consultant of Arima Genomics Inc. and cofounder of Epigenome Technologies, Inc. Chi and University of California San Diego are inventors of a filed patent. All other authors declare no competing interests.
This study is one of several published in special editions of Science and Science Advances. Additional studies in this package with UC San Diego-affiliated lead authors include:
- Epigenetic and 3D genome reprogramming during the aging of human hippocampus
- Human body single-cell atlas of three-dimensional genome organization and DNA methylation
- Single-cell analysis of the epigenome and 3D chromatin architecture in the human retina
