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

Institut de Pathologie [CHU Lille]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Pourcet, Benoit [Auteur]

Lestrelin, Réjane [Auteur]

Ravnskjaer, Kim [Auteur]
Lassailly, Guillaume [Auteur]

Haas, Joel [Auteur]

Mathurin, Philippe [Auteur]

Pattou, François [Auteur]
Dubuquoy, Laurent [Auteur]

Staels, Bart [Auteur]

Lefebvre, Philippe [Auteur]
Eeckhoute, Jérôme [Auteur]
Université de Lille
Institut Pasteur de Lille
Institut National de la Santé et de la Recherche Médicale [INSERM]
Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U 1011 [RNMCD]

Journal title :

Nature Communications

Pages :

5324

Publisher :

Nature Publishing Group

Publication date :

2022-12

ISSN :

2041-1723

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

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 ...
Show more >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.Show less >

Language :

Anglais

Popular science :

Non

ANR Project :

PreciNASH
ULNE
Identification et caractérisation d'un nouveau facteur de transcription controlant l'activation des cellules stellaires et la fibrose hépatique
L'activation métabolique des cellules dendritiques dans la steatopathie métabolique
Cibler les MEcanismes cellulaires du défaut de régénération pour le développement d'une médecine de précision pour l'hépatite ALcoolique.

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