TY  - JOUR
AU  - Cheng, Saifeng
AU  - Mittnenzweig, Markus
AU  - Mayshar, Yoav
AU  - Lifshitz, Aviezer
AU  - Dunjić, Marko
AU  - Rais, Yoach
AU  - Ben-Yair, Raz
AU  - Gehrs, Stephanie
AU  - Chomsky, Elad
AU  - Mukamel, Zohar
AU  - Rubinstein, Hernan
AU  - Schlereth, Katharina
AU  - Reines, Netta
AU  - Orenbuch, Ayelet-Hashahar
AU  - Tanay, Amos
AU  - Stelzer, Yonatan
TI  - The intrinsic and extrinsic effects of TET proteins during gastrulation.
JO  - Cell
VL  - 185
IS  - 17
SN  - 0092-8674
CY  - New York, NY
PB  - Elsevier
M1  - DKFZ-2022-01706
SP  - 3169-3185.e20
PY  - 2022
N1  - 2022 Aug 18;185(17):3169-3185.e20
AB  - Mice deficient for all ten-eleven translocation (TET) genes exhibit early gastrulation lethality. However, separating cause and effect in such embryonic failure is challenging. To isolate cell-autonomous effects of TET loss, we used temporal single-cell atlases from embryos with partial or complete mutant contributions. Strikingly, when developing within a wild-type embryo, Tet-mutant cells retain near-complete differentiation potential, whereas embryos solely comprising mutant cells are defective in epiblast to ectoderm transition with degenerated mesoderm potential. We map de-repressions of early epiblast factors (e.g., Dppa4 and Gdf3) and failure to activate multiple signaling from nascent mesoderm (Lefty, FGF, and Notch) as likely cell-intrinsic drivers of TET loss phenotypes. We further suggest loss of enhancer demethylation as the underlying mechanism. Collectively, our work demonstrates an unbiased approach for defining intrinsic and extrinsic embryonic gene function based on temporal differentiation atlases and disentangles the intracellular effects of the demethylation machinery from its broader tissue-level ramifications.
KW  - DNA demethylation (Other)
KW  - cell fate decisions (Other)
KW  - developmental biology (Other)
KW  - epigenetics (Other)
KW  - genome editing (Other)
KW  - mouse gastrulation (Other)
KW  - single-cell genomics (Other)
KW  - stem cells (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:35908548
DO  - DOI:10.1016/j.cell.2022.06.049
UR  - https://inrepo02.dkfz.de/record/180982
ER  -