| Title: |
TDG orchestrates ATF4-dependent gene transcription during retinoic acid-induced cell fate acquisition |
| Authors: |
Turpin, Marion; Madigou, Thierry; Bizot, Maud; Acker, Rachael; Avner, Stéphane; Benoît, Gérard; Braud, Martin; Fourgeux, Cynthia; Palierne, Gaëlle; Poschmann, Jeremie; Sawvell, Katie; Watrin, Erwan; Le Péron, Christine; Salbert, Gilles |
| Contributors: |
Institut de Génétique et Développement de Rennes (IGDR); Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes (Biosit : Biologie - Santé - Innovation Technologique); Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI); Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE); Nantes Université - pôle Santé; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ); This work was funded by the Centre National de la Recherche Scientifique (CNRS) and the University of Rennes. M.T. was a recipient of a Doctoral Fellowship from the University of Rennes. R.A. was a recipient of a Fullbright grant. K.S. was a recipient of a scholarship from the Northern Kentucky University STEM International Research and Scholarly Exchange Program. Funding to pay the Open Access publication charges for this article was provided by the CNRS. We thank L. Deleurme and A. Aimé for conducting cell sorting experiments at the Biosit cell sorting platform (https://biosit.univ-rennes.fr/cytometrie-en-flux-et-tri-cellulaire). We also thank E. Chevet and E. Lafont for the gift of p70S6K and Phospho-p70S6K antibodies, PA Bidaud-Meynard for the gift of rapamycin, and A. Sérandour for providing sequencing reagents. We are grateful to A. Laurent for MNase-seq library preparation and to S. Dréano for Sanger sequencing. Appreciation is extended to the Genomics Core Facility GenoA and the Bioinformatics Core Facility BiRD, both members of Biogenouest and France Genomique, as well as the Institut Français de Bioinformatique for their resources and technical support. The graphical abstract was created in BioRender. Salbert, G. (2026; https://BioRender.com/0wott6k. |
| Source: |
ISSN: 0305-1048. |
| Publisher Information: |
CCSD; Oxford University Press |
| Publication Year: |
2026 |
| Collection: |
Université de Nantes: HAL-UNIV-NANTES |
| Subject Terms: |
[SDV]Life Sciences [q-bio] |
| Description: |
International audience ; Acquisition of cell identity is associated with a remodeling of the epigenome in part through active DNA demethylation. The T:G mismatch DNA glycosylase (TDG) participates to this process by removing 5-methylcytosines that have been oxidized by Ten-Eleven-Translocation enzymes. Despite this well-defined molecular function, a comprehensive view of the biological function of TDG is still lacking, especially during cell differentiation. Here, we combined transcriptomic and epigenomic approaches in a Tdg knock-out epiblast stem-like cell model to decipher TDG function in pluripotent cells and their retinoic acid-induced progeny. We determined that TDG occupies a majority of active promoters, a large fraction of which are also engaged by the transcription factor ATF4. Consistently, neural fate commitment upon retinoic acid treatment is associated with a sustained expression of ATF4-dependent genes that relies on TDG-but not on its catalytic activity-in relation with a TDG-associated nucleosome positioning at promoters. We further evidenced that TDG maintains ATF4 pathway activity by positively regulating the mammalian target of rapamycin complex 1 (mTORC1), favoring neural cell fate commitment. These observations highlight the central role of TDG in cell differentiation and support a model linking metabolic reprogramming to cell fate acquisition. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/41773019; PUBMED: 41773019; PUBMEDCENTRAL: PMC12956359 |
| DOI: |
10.1093/nar/gkag152 |
| Availability: |
https://hal.science/hal-05537899; https://hal.science/hal-05537899v1/document; https://hal.science/hal-05537899v1/file/gkag152.pdf; https://doi.org/10.1093/nar/gkag152 |
| Rights: |
https://creativecommons.org/licenses/by-nc/4.0/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.1D83BC65 |
| Database: |
BASE |