Derepression of the epithelial transcription factor GRHL2 promotes direct hepatocyte-to-cholangiocyte transdifferentiation
The liver's regenerative capacity is underscored by the plasticity potential of adult hepatocytes. In this context, hepatocyte-to-cholangiocyte transdifferentiation (HCT) has been ascribed with pro-regenerative functions in animal models and is a feature of end-stage human chronic liver diseases. While dampened activities of hepatocyte identity transcription factors (TFs) underlay HCT, how the cholangiocyte transcriptional program is implemented is poorly defined. Here, we identify that HCT does not involve transitioning through a hepatoblast-like transcriptional program. Furthermore, we show that HCT primarily involves induction of the archetypal transcriptional program of monopolarized epithelial cells initially repressed in hepatocytes. Indeed, HCT requires relieving H3K27me3-mediated and polycomb-dependent epigenetic silencing of epithelial TF encoding genes including Grainyhead Like Transcription Factor 2 (GRHL2). Ectopic expression of GRHL2 in hepatocytes, including in vivo in the adult mouse liver, induces epithelial genes reminiscent of those activated during HCT. Finally, GRHL2 is detected in human hepatocytes undergoing HCT as evidenced using samples from end-stage chronic liver diseases. Hence, HCT is a process chiefly characterized by induction of a conventional epithelial transcriptional program originally lacking in hepatocytes promoted by derepression of the master epithelial TF GRHL2.
Authors
- Bart Staels (ORCID: https://orcid.org/0000-0002-3784-1503)
- Line Carolle Ntandja‐Wandji
- Ninon Very (ORCID: https://orcid.org/0000-0003-4250-5819)
- Mohamed Bou Saleh
- Noémie Legrand
- Lars Grøntved (ORCID: https://orcid.org/0000-0002-6735-8483)
- Anne Corlu
- Antonino Bongiovanni (ORCID: https://orcid.org/0000-0001-9876-2940)
- Clémence Boulet
- Viviane Gnemmi (ORCID: https://orcid.org/0000-0001-7403-4607)
- Guillaume Lasailly
- Philippe Lefèbvre (ORCID: https://orcid.org/0000-0002-9366-5129)
- Alexandre Berthier (ORCID: https://orcid.org/0000-0003-4153-4810)
- Loïc Guille (ORCID: https://orcid.org/0000-0002-8387-1092)
- Emmanuelle Leteurtre (ORCID: https://orcid.org/0000-0002-2118-0704)
- Pascal Loyer (ORCID: https://orcid.org/0000-0002-5656-2673)
- Cyril Sobolewski (ORCID: https://orcid.org/0000-0002-9404-6290)
- David Tulasne (ORCID: https://orcid.org/0000-0002-6764-7242)
- Dmitry Galinousky (ORCID: https://orcid.org/0000-0002-2522-6052)
- Laurent Dubuquoy (ORCID: https://orcid.org/0000-0003-3596-5497)
- Nicolaj I. Toft (ORCID: https://orcid.org/0000-0002-6885-6388)
- Alessandro Furlan (ORCID: https://orcid.org/0000-0001-6502-8416)
- Céline Gheeraert (ORCID: https://orcid.org/0000-0003-4096-6363)
- Julie Dubois‐Chevalier (ORCID: https://orcid.org/0000-0003-0471-752X)
- Jérôme Eeckhoute (ORCID: https://orcid.org/0000-0002-7222-9264)
- Solenne Taront
- Ludivine Vasseur
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- University of Southern Denmark (DK)
- Université de Lille (FR)
- Institut Pasteur de Lille (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Lille Inflammation Research International Center (FR)
- Centre Oscar Lambret (FR)
- Foie, Métabolisme, Cancer (FR)
- Institute for Translational Research in Inflammation (FR)
- CANTHER - Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers (FR)
- Université de Rennes (FR)
Publication Details
- Journal
- PLoS Biology
- Published
- 2025-12-12
- DOI
- https://doi.org/10.1371/journal.pbio.3003547
- Primary Topic
- Liver physiology and pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Université de Lille
- European Genomic Institute for Diabetes
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale
- Association Française pour l'Etude du Foie