DUX-miR-344-ZMYM2-Mediated Activation of MERVL LTRs Induces a Totipotent 2C-like State.
DUX-miR-344-ZMYM2-Mediated Activation of MERVL LTRs Induces a Totipotent 2C-like State.
复制标题
DUX-miR-344-ZMYM2 介导的 MERVL LTR 激活诱导全能 2C 样状态。
DOI：
10.1016/j.stem.2020.01.004
复制
发表时间：
2020-02-06
期刊：
影响因子：
23.9
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Yang F;Huang X;Zang R;Chen J;Fidalgo M;Sanchez-Priego C;Yang J;Caichen A;Ma F;Macfarlan T;Wang H;Gao S;Zhou H;Wang J
小鼠胚胎干细胞（ESC）偶尔表达植入前两细胞期（2C）转录本，包括MERVL内源性逆转录病毒和Zscan 4簇基因。这种2C样细胞（2CLC）可以有助于胚胎和胚胎外组织时，重新引入早期胚胎，虽然这种扩展的2CLC效力的分子机制仍然难以捉摸。我们研究了2CLC中的核小体占据率和基因表达，并确定miR-344为正控制2CLC效力的非编码分子。我们发现，内源性MERVL或miR-344-2单独的激活足以诱导2CLC，同时激活2C基因和扩大的效力。在机制上，miR-344被DUX激活并转录后抑制ZMYM 2及其伴侣LSD 1，ZMYM 2将LSD 1/HDAC辅阻遏物复合物募集到MERVL LTR进行转录抑制。一致地，Zmym 2的合子缺失损害了早期发育期间全能性到多能性的转变。我们的研究建立了以前未被认识到的DUX-miR-344-Zmym 2/Lsd 1轴，该轴控制MERVL用于扩增的干细胞效力。Wang和他的同事证明，通过内源性激活MERVL或miR-344可以获得扩增的干细胞潜能。在机制上，miR-344（DUX的直接转录靶标）通过抑制下游靶标Zmym 2激活内源性MERVL，所述下游靶标Zmym 2直接结合MERVL LTR并募集HDAC辅阻遏物用于转录抑制。
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. 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 via repressing downstream target Zmym2 that directly binds to MERVL LTRs and recruits HDAC corepressors for transcriptional repression.
登录
查看更多内容
影响因子：
64.8
作者：
Konermann S;Brigham MD;Trevino AE;Joung J;Abudayyeh OO;Barcena C;Hsu PD;Habib N;Gootenberg JS;Nishimasu H;Nureki O;Zhang F
通讯作者：
Zhang F
影响因子：
3.7
作者：
Gocke CB;Yu H
通讯作者：
Yu H
影响因子：
30.8
作者：
Guallar D;Bi X;Pardavila JA;Huang X;Saenz C;Shi X;Zhou H;Faiola F;Ding J;Haruehanroengra P;Yang F;Li D;Sanchez-Priego C;Saunders A;Pan F;Valdes VJ;Kelley K;Blanco MG;Chen L;Wang H;Sheng J;Xu M;Fidalgo M;Shen X;Wang J
通讯作者：
Wang J
影响因子：
7.7
作者：
Ancelin, Katia;Syx, Laurene;Heard, Edith
通讯作者：
Heard, Edith
影响因子：
20.6
作者：
Lu F;Zhang Y
通讯作者：
Zhang Y