Single-cell multiomics and chromatin structure reveal gene-regulatory dynamics in heart failure
Abstract
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.
Article Details
Journal Info
Science
American Association for the Advancement of Science
Authors (37)
Yang Xie
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Luca Tucciarone
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Elie N. Farah
Department of Medicine, Division of Cardiology, University of California San Diego, La Jolla, CA, USA.
Lei Chang
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Qian Yang
Thirupura S. Shankar
Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah, Salt Lake City, UT, USA.
Weston Elison
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Shaina Tran
Department of Medicine, Division of Cardiology, University of California San Diego, La Jolla, CA, USA.
Jovina Djulamsah
Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Audrey Lie
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Timothy Loe
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Alyssa R. Holman
Department of Medicine, Division of Cardiology, University of California San Diego, La Jolla, CA, USA.
Sierra Corban
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Justin Buchanan
Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Sainath Mamde
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Haowen Zhou
Department of Medicine, Division of Cardiology, University of California San Diego, La Jolla, CA, USA.
Ruth M. Elgamal
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Eleni Tseliou
Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah, Salt Lake City, UT, USA.
Vincent Huang
Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah, Salt Lake City, UT, USA.
Zhaoning Wang
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Jeffrey Huey-Chuan Chiu
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Rebecca Melton
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Emily Griffin
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Qingquan Zhang
Jacinta Lucero
Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Sutip Navankasattusas
Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah, Salt Lake City, UT, USA.
Daofeng Li
Chanrung Seng
Department of Genetics, The Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.
Eugin Destici
Department of Medicine, Division of Cardiology, University of California San Diego, La Jolla, CA, USA.
Craig H. Selzman
Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah, Salt Lake City, UT, USA.
Agnieszka D’Antonio-Chronowska
Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Ting Wang
Department of Radiation Oncology The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital Zhengzhou China
Allen Wang
Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Stavros G. Drakos
Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah, Salt Lake City, UT, USA.
Kyle J. Gaulton
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Bing Ren
Neil C. Chi