TDG orchestrates ATF4-dependent gene transcription during retinoic acid-induced cell fate acquisition

Turpin, M.; Madigou, T.; Bizot, M.; Acker, R.; Watrin, E.; Benoit, G.; Sawvell, K.; Avner, S.; Palierne, G.; Fourgeux, C.; Braud, M.; Poschmann, J.; Le Peron, C.; Salbert, G.

doi:10.1101/2024.04.01.587571

bioRxiv · 10.1101/2024.04.01.587571

TDG orchestrates ATF4-dependent gene transcription during retinoic acid-induced cell fate acquisition

Turpin, M.·Madigou, T.·Bizot, M.·Acker, R.·Watrin, E.·Benoit, G.·Sawvell, K.·Avner, S.·Palierne, G.·Fourgeux, C.·Braud, M.·Poschmann, J.·Le Peron, C.·Salbert, G.

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Abstract

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 (TET) 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 TDG-dependent sustained expression of ATF4-dependent genes, 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.

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Turpin, M., Madigou, T., Bizot, M., Acker, R., Watrin, E., Benoit, G., Sawvell, K., Avner, S., Palierne, G., Fourgeux, C., Braud, M., Poschmann, J., Le Peron, C., Salbert, G.. 2024-04-01. TDG orchestrates ATF4-dependent gene transcription during retinoic acid-induced cell fate acquisition. https://doi.org/10.1101/2024.04.01.587571

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