TET-Catalyzed 5-Hydroxymethylation Precedes HNF4A Promoter Choice during Differentiation of Bipotent Liver Progenitors

Pierre-Benoit Ancey (1) , Szilvia Ecsedi (1) , Marie-Pierre Lambert (2) , Fazlur Rahman Talukdar (1) , Marie-Pierre Cros (1) , Denise Glaise (3) , Diana Maria Narvaez (1) , Veronique Chauvet (1) , Zdenko Herceg (1) , Anne Corlu (3) , Hector Hernandez-Vargas (1)

1 CIRC - IARC - Centre International de Recherche contre le Cancer - International Agency for Research on Cancer
2 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
3 NuMeCan - Nutrition, Métabolismes et Cancer

Understanding the processes that govern liver progenitor cell differentiation has important implications for the design of strategies targeting chronic liver diseases, whereby regeneration of liver tissue is critical. Although DNA methylation (5mC) and hydroxymethylation (5hmC) are highly dynamic during early embryonic development, less is known about their roles at later stages of differentiation. Using an in vitro model of hepatocyte differentiation, we show here that 5hmC precedes the expression of promoter 1 (P1)-dependent isoforms of HNF4A, a master transcription factor of hepatocyte identity. 5hmC and HNF4A expression from P1 are dependent on ten-eleven translocation (TET) dioxygenases. In turn, the liver pioneer factor FOXA2 is necessary for TET1 binding to the P1 locus. Both FOXA2 and TETs are required for the 5hmC-related switch in HNF4A expression. The epigenetic event identified here may be a key step for the establishment of the hepatocyte program by HNF4A.

Mots clés: 5mC; DNA methylation; HNF4A; liver progenitor; 5hmC

Domaines: Embryologie et organogenèse

Pierre-Benoit Ancey, Szilvia Ecsedi, Marie-Pierre Lambert, Fazlur Rahman Talukdar, Marie-Pierre Cros, et al.. TET-Catalyzed 5-Hydroxymethylation Precedes HNF4A Promoter Choice during Differentiation of Bipotent Liver Progenitors. Stem Cell Reports, 2017, 9 (1), pp.264-278. ⟨10.1016/j.stemcr.2017.05.023⟩. ⟨hal-01578620⟩