Single-cell multiomics and chromatin structure reveal gene-regulatory dynamics in heart failure
Heart failure is a leading cause of morbidity and mortality, yet gene-regulatory mechanisms driving cell type-specific pathologic responses remain undefined. Here, we present the cell type-resolved transcriptomes, chromatin accessibility, histone modifications, and chromatin organization of 13 nonfailing and 23 failing human hearts across all cardiac chambers. Integrative analyses revealed dynamic changes in cell type composition, gene-regulatory programs, and chromatin organization, particularly in cardiomyocytes and fibroblasts. Mapping cell type-specific enhancer-gene interactions from these analyses enabled the illumination of likely causal genetic contributors to heart failure from genetic association data. Together, these findings provide multimodal gene-regulatory maps of the human heart in health and disease, offering a framework for designing precise, cell type-targeted therapies for treating heart failure.
Authors
- C. Neil (ORCID: https://orcid.org/0000-0003-2324-3796)
- Justin Buchanan (ORCID: https://orcid.org/0000-0001-5904-222X)
- Rebecca Melton (ORCID: https://orcid.org/0000-0003-3219-5773)
- Alyssa R. Holman (ORCID: https://orcid.org/0000-0002-6705-8034)
- Zhaoning Wang (ORCID: https://orcid.org/0000-0002-0290-4746)
- Yang Xie (ORCID: https://orcid.org/0000-0002-7453-6786)
- Sierra Corban
- Weston Elison (ORCID: https://orcid.org/0000-0002-5496-2972)
- Eugin Destici (ORCID: https://orcid.org/0000-0002-8472-1766)
- Anita Lie
- Shaina Tran (ORCID: https://orcid.org/0000-0003-2951-9730)
- Allen Wang (ORCID: https://orcid.org/0000-0001-9870-7888)
- Kyle J. Gaulton (ORCID: https://orcid.org/0000-0003-1318-7161)
- Stavros G. Drakos (ORCID: https://orcid.org/0000-0002-1223-327X)
- Luca Tucciarone (ORCID: https://orcid.org/0000-0002-0142-2171)
- Sutip Navankasattusas (ORCID: https://orcid.org/0000-0001-6293-5627)
- Sainath Mamde
- Bing Ren (ORCID: https://orcid.org/0000-0002-5435-1127)
- Daofeng Li (ORCID: https://orcid.org/0000-0001-7492-3703)
- Haowen Zhou (ORCID: https://orcid.org/0000-0001-9678-1865)
- Ruth M. Elgamal (ORCID: https://orcid.org/0000-0001-9183-9386)
- Elie N. Farah (ORCID: https://orcid.org/0000-0002-2412-0950)
- Agnieszka D’Antonio‐Chronowska (ORCID: https://orcid.org/0000-0003-1653-4106)
- Thirupura S. Shankar (ORCID: https://orcid.org/0000-0002-5009-2770)
- Ting Wang (ORCID: https://orcid.org/0000-0002-6800-242X)
- Qingquan Zhang (ORCID: https://orcid.org/0000-0002-2153-6491)
- Vincent Huang (ORCID: https://orcid.org/0000-0003-2079-2263)
- Lei Chang (ORCID: https://orcid.org/0000-0002-2606-3347)
- Chanrung Seng
- Jovina Djulamsah
- Jeffrey Huey-Chuan Chiu
- Jacinta Lucero (ORCID: https://orcid.org/0000-0001-7578-6624)
- Qian Yang (ORCID: https://orcid.org/0009-0004-1911-8874)
- Emily Griffin
- Eleni Tseliou
- Craig H. Selzman
- Timothy Loe
Institutions
- James S. McDonnell Foundation (US)
- Washington University in St. Louis (US)
- University of Utah (US)
- Columbia University Irving Medical Center (US)
- University of California San Diego (US)
- La Jolla Bioengineering Institute (US)
- New York Genome Center (US)
Publication Details
- Journal
- Science
- Published
- 2026-07-23
- DOI
- https://doi.org/10.1126/science.ady6893
- Primary Topic
- Cardiac Fibrosis and Remodeling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Foundation for the National Institutes of Health
- U.S. Department of Veterans Affairs
- Life Sciences Research Foundation
- Nora Eccles Treadwell Foundation
- National Institutes of Health
- National Heart, Lung, and Blood Institute