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Single-cell multi-omics profiling links dynamic DNA methylation to cell fate decisions during mouse early organogenesis.

Published version
Peer-reviewed

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Authors

Clark, Stephen J 
Argelaguet, Ricard 
Lohoff, Tim 
Krueger, Felix 
Drage, Deborah 

Abstract

BACKGROUND: Perturbation of DNA methyltransferases (DNMTs) and of the active DNA demethylation pathway via ten-eleven translocation (TET) methylcytosine dioxygenases results in severe developmental defects and embryonic lethality. Dynamic control of DNA methylation is therefore vital for embryogenesis, yet the underlying mechanisms remain poorly understood. RESULTS: Here we report a single-cell transcriptomic atlas from Dnmt and Tet mutant mouse embryos during early organogenesis. We show that both the maintenance and de novo methyltransferase enzymes are dispensable for the formation of all major cell types at E8.5. However, DNA methyltransferases are required for silencing of prior or alternative cell fates such as pluripotency and extraembryonic programmes. Deletion of all three TET enzymes produces substantial lineage biases, in particular, a failure to generate primitive erythrocytes. Single-cell multi-omics profiling moreover reveals that this is linked to a failure to demethylate distal regulatory elements in Tet triple-knockout embryos. CONCLUSIONS: This study provides a detailed analysis of the effects of perturbing DNA methylation on mouse organogenesis at a whole organism scale and affords new insights into the regulatory mechanisms of cell fate decisions.

Description

Keywords

Animals, DNA, DNA Methylation, Dioxygenases, Methyltransferases, Mice, Organogenesis

Journal Title

Genome Biol

Conference Name

Journal ISSN

1474-7596
1474-760X

Volume Title

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (203813/Z/16/Z)
Wellcome Trust (220379/Z/20/Z)
Medical Research Council (MC_PC_17230)