Tissue formation and organ homeostasis is achieved by precise coordination of proliferation and differentiation of stem cells and progenitors. While deregulation of these processes can result in degenerative disease or cancer, their molecular interplays remain unclear. Here we show that the switch of human pluripotent stem cell (hPSC) self-renewal to differentiation is associated with the induction of distinct cyclin dependent kinase inhibitors (CDKIs). In hPSCs, Activin/Nodal/TGFβ signalling maintains CDKIs in a poised state via SMAD2/3-NANOG-OCT4-EZH2-SNON transcriptional complex. Upon gradual differentiation, CDKIs are induced by successive transcriptional complexes between SMAD2/3-SMYD2 and developmental regulators such as EOMES, thereby lengthening the G1 phase. This, in turn, induces SMAD2/3 transcriptional activity by blocking its linker phosphorylation. Such SMAD2/3-CDKI positive feedback loops drive the exit from pluripotency and stepwise cell fate specification that could be harnessed for producing cells for therapeutic applications. Our study uncovers fundamental mechanisms how cell fate specification is interconnected to cell cycle dynamics and provides insight to autonomous circuitries governing tissue self-formation.

中文翻译：

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SMAD2/3-SMYD2 和发育转录因子与细胞周期抑制剂配合指导组织形成。


组织形成和器官稳态是通过干细胞和祖细胞增殖和分化的精确协调来实现的。虽然这些过程的放松管制可能导致退行性疾病或癌症，但它们的分子相互作用仍不清楚。在这里，我们证明人类多能干细胞（hPSC）自我更新向分化的转变与不同的细胞周期蛋白依赖性激酶抑制剂（CDKI）的诱导有关。在 hPSC 中，Activin/Nodal/TGFβ 信号传导通过 SMAD2/3-NANOG-OCT4-EZH2-SNON 转录复合物维持 CDKI 处于平衡状态。逐渐分化后，SMAD2/3-SMYD2 和 EOMES 等发育调节因子之间的连续转录复合物会诱导 CDKI，从而延长 G1 期。这反过来又通过阻断其接头磷酸化来诱导 SMAD2/3 转录活性。这种 SMAD2/3-CDKI 正反馈环路驱动多能性和逐步细胞命运规范的退出，可用于生产用于治疗应用的细胞。我们的研究揭示了细胞命运规范如何与细胞周期动力学相互关联的基本机制，并为控制组织自我形成的自主回路提供了见解。