DUX-miR-344-ZMYM2-Mediated Activation of MERVL LTRs Induces a Totipotent 2C-like State

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, althoug...

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Published in:	Cell stem cell Vol. 26; no. 2; pp. 234 - 250.e7
Main Authors:	Yang, Fan, Huang, Xin, Zang, Ruge, Chen, Jiayu, Fidalgo, Miguel, Sanchez-Priego, Carlos, Yang, Jihong, Caichen, Alexander, Ma, Fanglin, Macfarlan, Todd, Wang, Huayan, Gao, Shaorong, Zhou, Hongwei, Wang, Jianlong
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 06-02-2020
Subjects:	2C-like cells Animals Dux endogenous retrovirus Endogenous Retroviruses - genetics Gata2 Lsd1 MERVL Mice MicroRNAs - genetics miR-344 Mouse Embryonic Stem Cells totipotency Zmym2 Zygote miR-344 Lsd1 2C-like cells endogenous retrovirus Dux totipotency Zmym2 MERVL Gata2
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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. [Display omitted] •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 Wang and colleagues demonstrate that expanded stem cell potency can be obtained by endogenous activation of MERVL or miR-344. Mechanistically, miR-344, a direct transcriptional target of DUX, activates endogenous MERVL by repressing downstream target Zmym2 that directly binds to MERVL LTRs and recruits HDAC corepressors for transcriptional repression.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS F.Y., X.H., and R.Z. conceived, designed, conducted the studies and wrote the manuscript; M.F., C.S.-P., J.Y., A.C., F.M., T.M., H.W., H.Z. provided reagents and performed experiments; X.H. provided bioinformatics support; R.Z., J.C., and S.G. performed embryo injection experiments; J.W. conceived the project, designed the experiments, prepared and approved the manuscript. These authors contributed equally to this work.
ISSN:	1934-5909 1875-9777
DOI:	10.1016/j.stem.2020.01.004