TDG may support retinoic acid-induced neural fate commitment by sustaining -dependent transcription through promoter organization and activity.
Evidence
This transcriptomic and epigenomic cell-model study used Tdg knock-out epiblast stem-like cells and their retinoic acid-induced progeny to map TDG occupancy, ATF4-linked genes, nucleosome positioning, and mTORC1 regulation.
Caveat
The work is mechanistic evidence from a pluripotent cell differentiation model, so it does not establish organism-level developmental outcomes.
Simplified
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 . 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 (), 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.
Full Text
We can’t show the full text here under this license.
