Year: 2026
Type: preprint
Abstract: Summary Fibroblast activation drives organ failure across human diseases, yet its regulatory basis remains largely undefined. Here, we repressed 280 conserved disease-activated enhancers using CRISPR droplet sequencing (CROP-seq) in ∼550,000 fibroblasts, constructing a regulome of 15 gene programs governing the profibrotic state. Systematic TF perturbation converged on MEOX1 as a central regulator, and fibroblast-specific Meox1 deletion in mice improved cardiac function, reduced fibrosis, and rewired profibrotic fibroblasts toward quiescence in heart failure. Effector gene perturbation in human cardiac fibroblasts revealed distinct regulators of contractility, migration, and inflammatory signaling, and these programs were conserved across profibrotic states in human lung, liver, and skin. Simultaneous repression of just six enhancers using a multiplexed dCas12a-KRAB system collapsed the profibrotic network, suppressed migration and contraction, and rewired fibroblast paracrine signaling to attenuate macrophage inflammation. These findings define the regulatory logic of fibroblast plasticity and establish a new framework for reprogramming profibrotic cell states in disease.
Authors: Ada M. Zhu, Yeting Li, Haiwei Zhang, Brindha Rathinasabapathi, Bastien Cimarosti, Rangarajan Nadadur, Vee Xu, Yu Huang, Yuqian An, Kirsten Auclair, Alicja Mahr, Maya U. Sheth, Clara Youngna Lee, Chen Wang, Tracy Yamawaki, Angelo Pelonero, Arun Padmanabhan, Sanjeev S. Ranade, Jesse M. Engreitz, Brandon Ason, Chi-Ming Li, Simon Jackson, Junedh M. Amrute, Pawel F. Przytycki, Michael Alexanian
Institutions: Gladstone Institutes, Boston University, University of California, San Francisco, Sanford Burnham Prebys Medical Discovery Institute, Lucile Packard Children's Hospital, Stanford Medicine, Stanford University, Amgen (United States), Chan Zuckerberg Biohub San Francisco, Broad Institute, Stanford Cardiovascular Institute, Washington University in St. Louis, Max Delbrück Center, Heidelberg University
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Science Foundation, American Heart Association, Larry L. Hillblom Foundation, Amgen, Gladstone Institutes, Applebaum Foundation, Additional Ventures, Fondation Leducq, Novo Nordisk, National Institutes of Health, Genentech, Stanford Research Computing Center, Stanford University, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences
Awards: The Inflammatory-Fibrosis Axis in Ischemic Heart Failure: translating mechanisms into new diagnostics and therapeutics, G5211151649, Graduate Research Fellowship Program (GRFP), G6661425536, Targeting Pathological Cellular Crosstalk in Heart Failure, Chromatin Regulation of Immune Cells in Myocardial Inflammation, Epigenomic mechanisms of cardiac fibrosis and heart failure
OpenAlex ID: W7222848671