Derepression of the epithelial transcription factor GRHL2 promotes direct hepatocyte-to-cholangiocyte transdifferentiation
Year: 2025
Type: article
Abstract: 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.
Source: PLoS Biology
Authors: Ludivine Vasseur, Céline Gheeraert, Julie Dubois-Chevalier, Ninon Very, Loïc Guille, Mohamed Bou Saleh, Clémence Boulet, Cyril Sobolewski, Pascal Loyer, Alexandre Berthier, Noémie Legrand, Anne Corlu, Viviane Gnemmi, Guillaume Lasailly, Emmanuelle Leteurtre, Dmitry Galinousky, Antonino Bongiovanni, Solenne Taront, Nicolaj I. Toft, Lars Grøntved, David Tulasne, Alessandro Furlan, Line Carolle Ntandja-Wandji, Bart Staels, Philippe Lefebvre, Laurent Dubuquoy, Jérôme Eeckhoute
Institutions: Inserm, Université de Lille, Institut Pasteur de Lille, Centre Hospitalier Universitaire de Lille, Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires, Institute for Translational Research in Inflammation, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Nutrition, métabolismes et cancer, Université de Rennes, Centre National de la Recherche Scientifique, CANTHER - Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers, Plateformes Lilloises en Biologie et Santé, University of Southern Denmark, Centre Oscar Lambret
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,500
Awards: G1185957321, PreciDIAB Institute, the holistic approach of personal diabets care, G2084575248, G2354063855, G4412069605, EGID Diabetes Pole, G4656594441, G474489264, G5420063140, Identification and functional characterization of an unforeseen novel transcription factor controlling hepatic stellate cell activation and liver fibrosis, G6514784293, G7088779215, ULNE, G7371156854, Targeting cellular MEchanisms of altered regeneration for ALcoholic hepatitis precision medicine., G8083718527, G8429337512
OpenAlex ID: W4417304567