Laura Pilar Aguado‐Alvaro, Nerea Garitano, Wolfgang Esser‐Skala, Judith R. Sayers, Cynthia del Valle, Daniel Alameda, Julen Mendieta-Esteban, María Eréndira Calleja-Cervantes, Ainhoa Goñi‐Salaverri, Jon Zazpe, Anna Rosaria de Vito, Francesco P. Marchese, Diego Alignani, Juliana Cudini, Torsten Groß, Gregorio Rábago, Nisha Narayan, Laura Martínez, Sonia Martı́nez, Brian J.P. Huntly, Paul R. Riley, Arantxa González, Jake P. Taylor‐King, Nikolaus Fortelny, Beatriz Pelacho, David Lara‐Astiaso
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.