Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Massachusetts General Hospital Department of Molecular Biology, Boston, MA 02114, USA; Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Cell Stem Cell. 2018 Jun 1;22(6):851-864.e5. doi: 10.1016/j.stem.2018.04.021. Epub 2018 May 24.
The embryonic stem cell (ESC) transition from naive to primed pluripotency is marked by major changes in cellular properties and developmental potential. ISY1 regulates microRNA (miRNA) biogenesis, yet its role and relevance to ESC biology remain unknown. Here, we find that highly dynamic ISY1 expression during the naive-to-primed ESC transition defines a specific phase of "poised" pluripotency characterized by distinct miRNA and mRNA transcriptomes and widespread poised cell contribution to mouse chimeras. Loss- and gain-of-function experiments reveal that ISY1 promotes exit from the naive state and is necessary and sufficient to induce and maintain poised pluripotency, and that persistent ISY1 overexpression inhibits the transition from the naive to the primed state. We identify a large subset of ISY1-dependent miRNAs that can rescue the inability of miRNA-deficient ESCs to establish the poised state and transition to the primed state. Thus, dynamic ISY1 regulates poised pluripotency through miRNAs to control ESC fate.
胚胎干细胞（ESC）从原始态向初始态多能性的转变，其细胞特性和发育潜能发生了重大变化。ISY1 调节 microRNA（miRNA）的生物发生，但它在 ESC 生物学中的作用和相关性仍不清楚。在这里，我们发现，在原始态向初始态 ESC 转变过程中，ISY1 的高度动态表达定义了一个特定的“启动”多能性阶段，其特征是独特的 miRNA 和 mRNA 转录组，以及广泛的启动细胞对小鼠嵌合体的贡献。缺失和功能获得实验表明，ISY1 促进了从原始状态的退出，是诱导和维持启动多能性所必需和充分的，并且持续的 ISY1 过表达抑制了从原始状态向初始状态的转变。我们鉴定了一大类依赖于 ISY1 的 miRNA，它们可以挽救 miRNA 缺陷的 ESC 无法建立启动状态并向初始状态转变的能力。因此，动态的 ISY1 通过 miRNA 来调节启动多能性，从而控制 ESC 的命运。
