Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis.
Marie Bobowski-GerardClémence BouletFrancesco P ZummoJulie Dubois-ChevalierCéline GheeraertMohamed Bou SalehJean-Marc StrubAmaury FarceMaheul PlotonLoïc GuilleJimmy VandelAntonino BongiovanniNinon VeryEloïse WoitrainAudrey DeprinceFanny LalloyerEric BaugeLise FerriLine-Carolle Ntandja-WandjiAlexia K CotteCorinne GrangetteEmmanuelle VallezSarah CianféraniVioleta RaverdyRobert CaiazzoViviane GnemmiEmmanuelle LeteurtreBenoit PourcetRéjane PaumelleKim RavnskjaerGuillaume LassaillyJoel T HaasPhilippe MathurinFrancois PattouJosepmaria ArgemiBart StaelsPhilippe LefebvreJerome EeckhoutePublished in: Nature communications (2022)
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.
Keyphrases
- transcription factor
- liver fibrosis
- endothelial cells
- dna binding
- poor prognosis
- genome wide identification
- single cell
- gene expression
- stem cells
- induced apoptosis
- transforming growth factor
- bone marrow
- type diabetes
- high glucose
- induced pluripotent stem cells
- oxidative stress
- physical activity
- genome wide
- insulin resistance
- epithelial mesenchymal transition
- metabolic syndrome
- skeletal muscle
- diabetic rats
- long non coding rna
- anti inflammatory
- cell proliferation
- signaling pathway
- heat shock
- replacement therapy
- bioinformatics analysis