Cell Stem Cell
Volume 26, Issue 2, 6 February 2020, Pages 234-250.e7
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Article
DUX-miR-344-ZMYM2-Mediated Activation of MERVL LTRs Induces a Totipotent 2C-like State

https://doi.org/10.1016/j.stem.2020.01.004Get rights and content
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Highlights

  • Activation of endogenous MERVL or miR-344 induces 2CLCs with totipotency features

  • miR-344 directly silences Zmym2 and Lsd1 to activate MERVL and 2C-specific genes

  • Zmym2 zygotic depletion compromises embryo totipotency-to-pluripotency transition

  • DUX directly binds to the miR-344 cluster and activates its expression

Summary

Mouse embryonic stem cells (ESCs) sporadically express preimplantation two-cell-stage (2C) transcripts, including MERVL endogenous retrovirus and Zscan4 cluster genes. Such 2C-like cells (2CLCs) can contribute to both embryonic and extraembryonic tissues when reintroduced into early embryos, although the molecular mechanism underlying such an expanded 2CLC potency remains elusive. We examine global nucleosome occupancy and gene expression in 2CLCs and identified miR-344 as the noncoding molecule that positively controls 2CLC potency. We find that activation of endogenous MERVL or miR-344-2 alone is sufficient to induce 2CLCs with activation of 2C genes and an expanded potency. Mechanistically, miR-344 is activated by DUX and post-transcriptionally represses ZMYM2 and its partner LSD1, and ZMYM2 recruits LSD1/HDAC corepressor complex to MERVL LTR for transcriptional repression. Consistently, zygotic depletion of Zmym2 compromises the totipotency-to-pluripotency transition during early development. Our studies establish the previously unappreciated DUX-miR-344-Zmym2/Lsd1 axis that controls MERVL for expanded stem cell potency.

Keywords

endogenous retrovirus
MERVL
miR-344
Zmym2
Lsd1
Dux
Gata2
2C-like cells
totipotency

Cited by (0)

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Present address: Department of Medicine, Columbia Center for Human Development, Columbia University Irving Medical Center, New York, NY 10032, USA

8

These authors contributed equally to this work

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