Disabling de novo DNA methylation in embryonic stem cells allows an illegitimate fate trajectory
Masaki Kinoshita, Meng Amy Li, M. Barber, W Mansfield, Sabine Dietmann, Austin Smith
Abstract
Significance Mammalian DNA is widely modified by methylation of cytosine residues. This modification is added to DNA during early development. If methylation is prevented, the embryo dies by midgestation with multiple abnormalities. In this study we found that stem cells lacking the DNA methylation enzymes do not differentiate efficiently into cell types of the embryo and are diverted into producing placental cells. This switch in cell fate is driven by a transcription factor, Ascl2, which should only be produced in the placenta. In the absence of DNA methylation, the Ascl2 gene is misexpressed. Removing Ascl2 redirects embryonic fate but not full differentiation potential, suggesting that methylation acts at multiple developmental transitions to restrict activation of disruptive genes.