Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300
Williams LM., McCann FE., Cabrita MA., Layton T., Cribbs A., Knezevic B., Fang H., Knight J., Zhang M., Fischer R., Bonham S., Steenbeek LM., Yang N., Sood M., Bainbridge C., Warwick D., Harry L., Davidson D., Xie W., Sundstrӧm M., Feldmann M., Nanchahal J.
Significance Fibrosis remains a major unmet medical need as therapeutic targets discovered in animal models have failed to translate. A major challenge for identifying novel targets is the limited availability of early-stage human disease tissue. Here, we utilize Dupuytren’s disease (DD), a common localized fibrotic disorder, to evaluate the impact of epigenetic regulation of myofibroblasts and identify potential tractable targets in human fibrosis. We demonstrate that the epigenetic regulator CREBBP/EP300 is a critical determinant of the profibrotic phenotype. Furthermore, we identify collagen VI to be a key downstream target of CREBBP/EP300 and reveal valuable insights in the role it plays in key profibrotic functions, including contractile force, chemotaxis, and wound healing, and hence its potential as a therapeutic target.