Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis

Marie Bobowski-Gerard, Clémence Boulet, Francesco P. Zummo, Julie Dubois-Chevalier, Céline Gheeraert, Mohamed Bou Saleh, Jean-Marc Strub, Amaury Farce, Maheul Ploton, Loïc Guille, Jimmy Vandel, Antonino Bongiovanni, Ninon Very, Eloïse Woitrain, Audrey Deprince, Fanny Lalloyer, Eric Bauge, Lise Ferri, Line-Carolle Ntandja-Wandji, Alexia K. Cotte, Corinne Grangette, Emmanuelle Vallez, Sarah Cianférani, Violeta Raverdy, Robert Caiazzo, Viviane Gnemmi, Emmanuelle Leteurtre, Benoit Pourcet, Réjane Paumelle, Kim Ravnskjaer, Guillaume Lassailly, Joel T. Haas, Philippe Mathurin, François Pattou, Laurent Dubuquoy, Bart Staels, Philippe Lefebvre and Jérôme Eeckhoute ()
Additional contact information
Marie Bobowski-Gerard: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Clémence Boulet: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Francesco P. Zummo: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Julie Dubois-Chevalier: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Céline Gheeraert: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Mohamed Bou Saleh: Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation
Jean-Marc Strub: Laboratoire de Spectrométrie de Masse BioOrganique, CNRS UMR7178, Univ Strasbourg, IPHC
Amaury Farce: Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation
Maheul Ploton: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Loïc Guille: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Jimmy Vandel: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Antonino Bongiovanni: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille
Ninon Very: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Eloïse Woitrain: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Audrey Deprince: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Fanny Lalloyer: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Eric Bauge: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Lise Ferri: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Line-Carolle Ntandja-Wandji: Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation
Alexia K. Cotte: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Corinne Grangette: U1019-UMR 9017-CIIL-Centre d’Infection et d’Immunité de Lille, Institut Pasteur de Lille, Université de Lille
Emmanuelle Vallez: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Sarah Cianférani: Laboratoire de Spectrométrie de Masse BioOrganique, CNRS UMR7178, Univ Strasbourg, IPHC
Violeta Raverdy: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Robert Caiazzo: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Viviane Gnemmi: Centre Hospitalier Universitaire de Lille, Université de Lille
Emmanuelle Leteurtre: Centre Hospitalier Universitaire de Lille, Université de Lille
Benoit Pourcet: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Réjane Paumelle: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Kim Ravnskjaer: University of Southern Denmark
Guillaume Lassailly: Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation
Joel T. Haas: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Philippe Mathurin: Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation
François Pattou: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Laurent Dubuquoy: Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation
Bart Staels: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Philippe Lefebvre: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille
Jérôme Eeckhoute: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract Tissue 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.

Date: 2022
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DOI: 10.1038/s41467-022-33063-9

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