Open AccessDisabling de novo DNA methylation in embryonic stem cells allows an illegitimate fate trajectory
Author(s) -
Masaki Kinoshita,
Meng Amy Li,
M. Barber,
William Mansfield,
Sabine Dietmann,
Austin Smith
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2109475118
Subject(s) - biology , dna methylation , epigenetics , embryonic stem cell , methyltransferase , epiblast , stem cell , microbiology and biotechnology , trophoblast , transdifferentiation , dna methyltransferase , genetics , methylation , dna , gene , placenta , gene expression , pregnancy , gastrulation , fetus
Genome remethylation is essential for mammalian development but specific reasons are unclear. Here we examined embryonic stem (ES) cell fate in the absence of de novo DNA methyltransferases. We observed that ES cells deficient for both Dnmt3a and Dnmt3b are rapidly eliminated from chimeras. On further investigation we found that in vivo and in vitro the formative pluripotency transition is derailed toward production of trophoblast. This aberrant trajectory is associated with failure to suppress activation of Ascl2 Ascl2 encodes a bHLH transcription factor expressed in the placenta. Misexpression of Ascl2 in ES cells provokes transdifferentiation to trophoblast-like cells. Conversely, Ascl2 deletion rescues formative transition of Dnmt3a/b mutants and improves contribution to chimeric epiblast. Thus, de novo DNA methylation safeguards against ectopic activation of Ascl2 However, Dnmt3a/b -deficient cells remain defective in ongoing embryogenesis. We surmise that multiple developmental transitions may be secured by DNA methylation silencing potentially disruptive genes.