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Nat Cell Biol. 2019 Jul;21(7):835-844. doi: 10.1038/s41556-019-0343-0. Epub 2019 Jun 17.

Myc and Dnmt1 impede the pluripotent to totipotent state transition in embryonic stem cells.

Fu X1,2,3,4, Wu X1,2,3,4, Djekidel MN1,2,3,4, Zhang Y5,6,7,8.

Author information

1
Howard Hughes Medical Institute, Boston, MA, USA.
2
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
3
Harvard Stem Cell Institute, Boston, MA, USA.
4
Department of Genetics, Harvard Medical School, Boston, MA, USA.
5
Howard Hughes Medical Institute, Boston, MA, USA. yzhang@genetics.med.harvard.edu.
6
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. yzhang@genetics.med.harvard.edu.
7
Harvard Stem Cell Institute, Boston, MA, USA. yzhang@genetics.med.harvard.edu.
8
Department of Genetics, Harvard Medical School, Boston, MA, USA. yzhang@genetics.med.harvard.edu.

Abstract

Totipotency refers to the ability of a cell to generate all of the cell types of an organism. Unlike pluripotency, the establishment of totipotency is poorly understood. In mouse embryonic stem cells, Dux drives a small percentage of cells into a totipotent state by expressing 2-cell-embryo-specific transcripts. To understand how this transition takes place, we performed single-cell RNA-seq, which revealed a two-step transcriptional reprogramming process characterized by downregulation of pluripotent genes in the first step and upregulation of the 2-cell-embryo-specific elements in the second step. To identify factors controlling the transition, we performed a CRISPR-Cas9-mediated screen, which revealed Myc and Dnmt1 as two factors preventing the transition. Mechanistic studies demonstrate that Myc prevents downregulation of pluripotent genes in the first step, while Dnmt1 impedes 2-cell-embryo-specific gene activation in the second step. Collectively, the findings of our study reveal insights into the establishment and regulation of the totipotent state in mouse embryonic stem cells.

PMID:
31209294
DOI:
10.1038/s41556-019-0343-0

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