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

Author

Listed:
  • 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
    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)

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.

Suggested Citation

  • 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 Vand, 2022. "Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33063-9
    DOI: 10.1038/s41467-022-33063-9
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    References listed on IDEAS

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