Eukaryotic chaperone CCT5 or CCT7: a novel target for the regulation of embryonic stem cell state transition

A deeper understanding of the molecular mechanisms underlying the transition to the totipotent state will broaden the foundations of developmental biology, and the underlying mechanisms of early cell fate decisions have been an important topic of investigation. Based on the previous sequencing data of different mouse early embryonic development, 236 and 267 factors were identified to be continuously up-regulated at stages of mouse early embryonic development (with at least two-fold change in the next stage compared with the previous stage), and the core key factors CCT5 and CCT7 were selected. CCT5 and CCT7, as important members of the CCT family of chaperone proteins, are key regulators of telomerase transport, and their depletion will lead to the loss of TCAB1 protein and impair telomere maintenance. However, their role in the state transition of embryonic stem cells (ESCs) needs further investigation. Here, we show that defects in CCT5 or CCT7 affect the maintenance of telomere length, which in turn activates DNA damage pathways, induces epigenetic reprogramming, promotes cells into a state of enhanced plasticity and promotes the activation of repeat sequences and 2C gene programs to generate universal 2-cell-like cells. Thus, CCT5 and CCT7 may be epigenetic barriers to the transition from pluripotency to the totipotent state. At the same time, CCT5 or CCT7 may activate WNT signaling pathway by promoting β-catenin nuclear translocation, promote the expression of specific factors such as Esrrb, and regulate the pluripotent state of ESCs.