Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300
Lynn Williams, Fiona E. McCann, Marisa Cabrita, T. B. Layton, Adam P. Cribbs, Bogdan Knezevic, Hai Fang, Julian C. Knight, Mingjun Zhang, Román Fischer, Sarah Bonham, Leenart M. Steenbeek, Nan Yang, Manu Sood, L.C. Bainbridge, David Warwick, Lorraine Harry, Dominique Davidson, Weilin Xie, M. Sundström, Marc Feldmann, Jagdeep Nanchahal
Abstract
Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren's nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.