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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 5324 |
| Tidsskrift | Nature Communications |
| Vol/bind | 13 |
| Sider (fra-til) | 5324 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 10. sep. 2022 |
Bibliografisk note
Funding Information:The authors are indebted to Julien Devassine and Kim Letten of the EOPS2 animal facility (Plateformes Lilloises en Biologie et Santé (PLBS) - UMS 2014 - US 41, Univ. Lille), Sophie Salomé and Nathalie Jouy of the BioImaging Center Lille (BICeL) platform (Plateformes Lilloises en Biologie et Santé (PLBS) - UMS 2014 - US 41, Univ. Lille) for their assistance. The authors also would like to thank members of Inserm U1011 including Drs M. Johanns, L. L’Homme, N. Hennuyer, X. Maréchal, M. Rosa and M. Gimenez as well as F. Maggiotto (INFINITE, Lille) for technical help or helpful discussions. This work was supported by the Agence Nationale de la Recherche (ANR) grants “HSCreg” (ANR-21-CE14-0032), “MEdicAL” (ANR-21-CE17-0016), “DeCodeNASH” (ANR-20-CE14-0034), “PreciNASH” (ANR-16-RHUS-0006-PreciNASH), French Proteomic Infrastructure (ProFI; ANR-10-INBS-08–03) and “European Genomic Institute for Diabetes” E.G.I.D. (ANR-10-LABX-0046), a French State fund managed by ANR under the frame program Investissements d’Avenir I-SITE ULNE/ANR-16-IDEX-0004 ULNE. This project was also co-funded by The European Union under the European Regional Development Fund (ERDF) and by the Hauts de France Regional Council (contract 20000007 and contract 17003781), the MEL (contract_2020_ESR_02 and contract_2016_ESR_05) and the French State (contract no. 2019-R3-CTRL_IPL_Phase3 and contract no. 2017-R3-CTRL-Phase 1). Work in INFINITE was supported by a grant from the Fondation Recherche Médicale (FRM) (Equipe labellisée, EQU202003010299). BS is a recipient of an Advanced ERC Grant (694717).
Funding Information:
The authors are indebted to Julien Devassine and Kim Letten of the EOPS2 animal facility (Plateformes Lilloises en Biologie et Santé (PLBS) - UMS 2014 - US 41, Univ. Lille), Sophie Salomé and Nathalie Jouy of the BioImaging Center Lille (BICeL) platform (Plateformes Lilloises en Biologie et Santé (PLBS) - UMS 2014 - US 41, Univ. Lille) for their assistance. The authors also would like to thank members of Inserm U1011 including Drs M. Johanns, L. L’Homme, N. Hennuyer, X. Maréchal, M. Rosa and M. Gimenez as well as F. Maggiotto (INFINITE, Lille) for technical help or helpful discussions. This work was supported by the Agence Nationale de la Recherche (ANR) grants “HSCreg” (ANR-21-CE14-0032), “MEdicAL” (ANR-21-CE17-0016), “DeCodeNASH” (ANR-20-CE14-0034), “PreciNASH” (ANR-16-RHUS-0006-PreciNASH), French Proteomic Infrastructure (ProFI; ANR-10-INBS-08–03) and “European Genomic Institute for Diabetes” E.G.I.D. (ANR-10-LABX-0046), a French State fund managed by ANR under the frame program Investissements d’Avenir I-SITE ULNE/ANR-16-IDEX-0004 ULNE. This project was also co-funded by The European Union under the European Regional Development Fund (ERDF) and by the Hauts de France Regional Council (contract 20000007 and contract 17003781), the MEL (contract_2020_ESR_02 and contract_2016_ESR_05) and the French State (contract no. 2019-R3-CTRL_IPL_Phase3 and contract no. 2017-R3-CTRL-Phase 1). Work in INFINITE was supported by a grant from the Fondation Recherche Médicale (FRM) (Equipe labellisée, EQU202003010299). BS is a recipient of an Advanced ERC Grant (694717).
Publisher Copyright:
© 2022, The Author(s).