Identification of epigenetic regulators of fibrotic transformation in cardiac fibroblasts through bulk and single-cell CRISPR screens
Year: 2025
Type: article
Abstract: 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.
Source: Nature Communications
Authors: Laura Pilar Aguado-Alvaro, Nerea Garitano, Wolfgang Esser-Skala, Judy Sayers, Cynthia del Valle, Daniel Alameda, Julen Mendieta-Esteban, Maria Erendira Calleja-Cervantes, Ainhoa Goñi-Salaverri, Jon Zazpe, Anna Rosaria de Vito, Francesco Marchese, Diego Alignani, Juliana Cudini, Torsten Gross, Gregorio Rábago, Nisha Narayan, Laura Martinez, Sonia Martinez, Brian Huntly, Paul Riley, Arantxa Gonzalez, Jake P. Taylor-King, Nikolaus Fortelny, Beatriz Pelacho, David Lara-Astiaso
Institutions: Navarre Institute of Health Research, Centro de Investigación Médica Aplicada, Universidad de Navarra, University of Salzburg, University of Oxford, Andalusian Centre for Nanomedicine and Biotechnology, Instituto de Investigación Biomédica de Málaga, Clinica Universidad de Navarra, Wellcome/MRC Cambridge Stem Cell Institute, University of Cambridge, Instituto de Salud Carlos III, Centro de Investigación en Red en Enfermedades Cardiovasculares, Arc Research Institute, Wellcome Trust
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W4416724770