Identification of epigenetic regulators of fibrotic transformation in cardiac fibroblasts through bulk and single-cell CRISPR screens
Cardiac fibrosis is mediated by the persistent activity of myofibroblasts, which differentiates from resident cardiac fibroblasts in response to tissue damage and stress signals. The signaling pathways and transcription factors regulating fibrotic transformation have been thoroughly studied. In contrast, the roles of chromastin factors in myofibroblast differentiation and their contribution to pathogenic cardiac fibrosis remain poorly understood. Here, we combined bulk and single-cell CRISPR screens to characterize the roles of chromatin factors in the fibrotic transformation of primary cardiac fibroblasts. We uncover strong regulators of fibrotic states including Srcap and Kat5 chromatin remodelers. We confirm that these factors are required for functional processes underlying fibrosis including collagen synthesis and cell contractility. Using chromatin profiling in perturbed cardiac fibroblasts, we demonstrate that pro-fibrotic chromatin complexes facilitate the activity of well-characterized pro-fibrotic transcription factors. Finally, we show that KAT5 inhibition alleviates fibrotic responses in patient-derived human fibroblasts.
Authors
- Arantxa González (ORCID: https://orcid.org/0000-0001-5986-6528)
- María Eréndira Calleja-Cervantes (ORCID: https://orcid.org/0000-0003-0688-0793)
- Laura Pilar Aguado‐Alvaro (ORCID: https://orcid.org/0000-0003-3267-9313)
- Cynthia del Valle
- Julen Mendieta-Esteban (ORCID: https://orcid.org/0000-0002-5834-7643)
- Brian J.P. Huntly (ORCID: https://orcid.org/0000-0003-0312-161X)
- Diego Alignani (ORCID: https://orcid.org/0000-0003-0241-1375)
- Gregorio Rábago (ORCID: https://orcid.org/0000-0003-1936-6881)
- Juliana Cudini (ORCID: https://orcid.org/0000-0002-8420-0362)
- Judith R. Sayers (ORCID: https://orcid.org/0000-0003-2306-0607)
- Beatriz Pelacho (ORCID: https://orcid.org/0000-0002-0411-7164)
- Sonia Martı́nez (ORCID: https://orcid.org/0000-0003-2230-7794)
- Nikolaus Fortelny (ORCID: https://orcid.org/0000-0003-4025-9968)
- Jon Zazpe
- Jake P. Taylor‐King (ORCID: https://orcid.org/0000-0002-1025-0041)
- Nerea Garitano
- Wolfgang Esser‐Skala (ORCID: https://orcid.org/0000-0002-7350-4045)
- Nisha Narayan (ORCID: https://orcid.org/0000-0002-4106-2166)
- Ainhoa Goñi‐Salaverri (ORCID: https://orcid.org/0000-0003-0425-1520)
- Francesco P. Marchese (ORCID: https://orcid.org/0000-0002-6028-117X)
- Daniel Alameda (ORCID: https://orcid.org/0000-0002-6598-7163)
- Paul Richard Riley (ORCID: https://orcid.org/0000-0002-9862-7332)
- Torsten Groß
- David Lara‐Astiaso (ORCID: https://orcid.org/0000-0001-8686-4675)
- Laura Martínez (ORCID: https://orcid.org/0000-0003-0763-3997)
- Anna Rosaria de Vito
Institutions
- Southern California Institute of Architecture (US)
- University of Salzburg (AT)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Instituto de Salud Carlos III (ES)
- University of Oxford (GB)
- Centro de Investigación en Red en Enfermedades Cardiovasculares (ES)
- Navarre Institute of Health Research (ES)
- Clinica Universidad de Navarra (ES)
- Unfallkrankenhaus Salzburg (AT)
- Instituto de Investigación Biomédica de Málaga (ES)
- Universidad de Navarra (ES)
- Medical Research Council (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-26
- DOI
- https://doi.org/10.1038/s41467-025-66597-9
- Citations
- 1
- Primary Topic
- Cardiac Fibrosis and Remodeling
- Type
- article
- Field-Weighted Citation Impact
- 1.39