Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis
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Published:2022-09-10
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Bobowski-Gerard MarieORCID, Boulet Clémence, Zummo Francesco P., Dubois-Chevalier Julie, Gheeraert Céline, Bou Saleh Mohamed, Strub Jean-Marc, Farce AmauryORCID, Ploton MaheulORCID, Guille LoïcORCID, Vandel Jimmy, Bongiovanni AntoninoORCID, Very NinonORCID, Woitrain Eloïse, Deprince Audrey, Lalloyer Fanny, Bauge Eric, Ferri Lise, Ntandja-Wandji Line-Carolle, Cotte Alexia K., Grangette Corinne, Vallez Emmanuelle, Cianférani SarahORCID, Raverdy Violeta, Caiazzo Robert, Gnemmi Viviane, Leteurtre Emmanuelle, Pourcet Benoit, Paumelle Réjane, Ravnskjaer KimORCID, Lassailly Guillaume, Haas Joel T.ORCID, Mathurin Philippe, Pattou FrançoisORCID, Dubuquoy LaurentORCID, Staels BartORCID, Lefebvre Philippe, Eeckhoute JérômeORCID
Abstract
AbstractTissue injury triggers activation of mesenchymal lineage cells into wound-repairing myofibroblasts, whose unrestrained activity leads to fibrosis. Although this process is largely controlled at the transcriptional level, whether the main transcription factors involved have all been identified has remained elusive. Here, we report multi-omics analyses unraveling Basonuclin 2 (BNC2) as a myofibroblast identity transcription factor. Using liver fibrosis as a model for in-depth investigations, we first show that BNC2 expression is induced in both mouse and human fibrotic livers from different etiologies and decreases upon human liver fibrosis regression. Importantly, we found that BNC2 transcriptional induction is a specific feature of myofibroblastic activation in fibrotic tissues. Mechanistically, BNC2 expression and activities allow to integrate pro-fibrotic stimuli, including TGFβ and Hippo/YAP1 signaling, towards induction of matrisome genes such as those encoding type I collagen. As a consequence, Bnc2 deficiency blunts collagen deposition in livers of mice fed a fibrogenic diet. Additionally, our work establishes BNC2 as potentially druggable since we identified the thalidomide derivative CC-885 as a BNC2 inhibitor. Altogether, we propose that BNC2 is a transcription factor involved in canonical pathways driving myofibroblastic activation in fibrosis.
Funder
Agence Nationale de la Recherche
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference116 articles.
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