The intrinsic and extrinsic effects of TET proteins during gastrulation.
DNA demethylation
cell fate decisions
developmental biology
epigenetics
genome editing
mouse gastrulation
single-cell genomics
stem cells
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
18 08 2022
18 08 2022
Historique:
received:
14
10
2021
revised:
18
04
2022
accepted:
25
06
2022
pubmed:
1
8
2022
medline:
24
8
2022
entrez:
31
7
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35908548
pii: S0092-8674(22)00842-X
doi: 10.1016/j.cell.2022.06.049
pmc: PMC9432429
pii:
doi:
Substances chimiques
Dppa4 protein, mouse
0
Nuclear Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3169-3185.e20Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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