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

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DUX-miR-344-ZMYM2-Mediated Activation of MERVL LTRs Induces a Totipotent 2C-like State.
Cell Stem Cell ( IF 19.8 ) Pub Date : 2020-02-06 , DOI: 10.1016/j.stem.2020.01.004
Fan Yang ₁ , Xin Huang ₂ , Ruge Zang ₃ , Jiayu Chen ₄ , Miguel Fidalgo ₅ , Carlos Sanchez-Priego ₂ , Jihong Yang ₂ , Alexander Caichen ₂ , Fanglin Ma ₁ , Todd Macfarlan ₆ , Huayan Wang ₇ , Shaorong Gao ₄ , Hongwei Zhou ₂ , Jianlong Wang ₈

Affiliation

The Black Family Stem Cell Institute and Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Animal Biotechnology, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.
The Black Family Stem Cell Institute and Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
The Black Family Stem Cell Institute and Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Frontier Science Center for Stem Cell Research, Ministry of Education of China, Tongji University, Shanghai 200092, China.
Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Frontier Science Center for Stem Cell Research, Ministry of Education of China, Tongji University, Shanghai 200092, China.
The Black Family Stem Cell Institute and Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; CiMUS, Universidade de Santiago de Compostela-Health Research Institute (IDIS), Santiago de Compostela 15782, Spain.
The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Department of Animal Biotechnology, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.
The Black Family Stem Cell Institute and Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

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.

中文翻译：

DUX-miR-344-ZMYM2介导的MERVL LTR的激活诱导了全能2C样状态。

小鼠胚胎干细胞（ESCs）偶尔表达植入前的两细胞阶段（2C）转录本，包括MERVL内源性逆转录病毒和Zscan4簇基因。当重新引入早期胚胎时，这种2C样细胞（2CLC）可以对胚胎和胚外组织都有贡献，尽管这种扩展的2CLC效力的分子机制仍然难以捉摸。我们检查了2CLCs中的全球核小体占有率和基因表达，并将miR-344鉴定为积极控制2CLC效能的非编码分子。我们发现，单独激活内源性MERVL或miR-344-2足以诱导具有2C基因激活和扩展效能的2CLC。从机制上讲，miR-344由DUX激活，转录后抑制ZMYM2及其伙伴LSD1，ZMYM2将LSD1 / HDAC核心复合物招募至MERVL LTR进行转录抑制。一致地，Zmym2的合子耗竭损害了早期发育期间的全能到多能性的转变。我们的研究建立了以前未曾认识到的DUX-miR-344-Zmym2 / Lsd1轴，该轴控制MERVL来扩大干细胞的效力。

更新日期：2020-02-20

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