Cell-specific FUS loss enhances ageing-associated transcriptional elongation in lung fibrosis
Year: 2026
Type: preprint
Abstract: Summary Idiopathic pulmonary fibrosis (IPF) is an age-related, lethal lung disease affecting over 3 million people worldwide. During aging, impairment of diverse molecular processes compromises cellular homeostasis. Eukaryotic cells adapt to this ageing-associated stress by large-scale transcriptome changes affecting the expression of genes involved in signaling, protein homeostasis, cell plasticity and immune response. The molecular mechanisms regulating extensive transcriptome rearrangements leading to senescence in specific cell types of IPF lungs remain sparely investigated. Here we uncover fundamental molecular mechanisms underlying cellular senescence by integrative analysis of multi-omics studies and functional experiments monitoring fibrotic and senescence hallmarks in primary lung fibroblasts from control and IPF patients. Loss-of-function of the DNA/RNA binding protein fused in sarcoma (FUS) in control fibroblasts enhanced fibrotic and senescence hallmarks resembling IPF fibroblasts. Dissecting the molecular mechanisms, reduced FUS levels in IPF fibroblasts abolished R-loop formation at transcription start sites (TSS), leading to increased RNA polymerase II (Pol II) recruitment and its phosphorylation at serine 2, resulting in enhanced translocation speed of elongating Pol II and increased expression of fibrosis-and senescence-related genes. Summarizing, FUS maintains low Pol II processivity in control fibroblasts by stabilizing R-loops at TSS, acting as a gatekeeper of fibrotic and age-associated transcriptional programs.
Authors: Diana G. Rogel-Ayala, Julio Cordero, Héctor A. Aguirre-Alarcón, Karla Rubio, Guruprasadh Swaminathan, Naceur Charif, Natalia de Isla, Witold Szymanski, Gowthami Kolluru Venkataswamy Reddy, Peter Braubach, Samina Mahmood, Stefan Günther, Miguel N. Rivera, Johannes Graumann, Thomas Braun, Malgorzata Wygrecka, Gergana Dobreva, Guillermo Barreto
Institutions: Centre National de la Recherche Scientifique, Max Planck Institute for Heart and Lung Research, Ingénierie Moléculaire, Cellulaire et Physiopathologie, Université de Lorraine, Heidelberg University, German Centre for Cardiovascular Research, Medizinische Fakultät Mannheim, Harvard University, Massachusetts General Hospital, Benemérita Universidad Autónoma de Puebla, Philipps University of Marburg, Justus-Liebig-Universität Gießen, German Center for Lung Research, Medizinische Hochschule Hannover, Max Delbrück Center
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7221124586