Chaperonin proteins CCT5 and CCT7 epigenetically restrict the transition from pluripotency to totipotency in embryonic stem cells.

As members of the CCT family, CCT5 and CCT7 play pivotal roles in telomerase trafficking, with their depletion resulting in TCAB1 protein loss and impaired telomere maintenance. However, their functional significance in embryonic stem cells (ESCs) state transitions remains incompletely understood. Here, we demonstrate that CCT5 or CCT7 deficiency disrupts telomere length homeostasis, triggering DNA damage response pathways and inducing epigenetic reprogramming. This cascade enhances cellular plasticity, activates repeat elements and 2-cell transcriptional programs, and facilitates the generation of 2-cell-like cells, suggesting that CCT5 and CCT7 may serve as epigenetic barriers restricting the transition from pluripotency to totipotency. Additionally, CCT5/7 stabilizes pluripotency through Wnt/β-catenin signaling: CCT7 directly binds β-catenin to facilitate nuclear translocation, while CCT5 dissociates E-cadherin/β-catenin complexes. These findings underscore the dual role of CCT5 and CCT7 in maintaining telomere integrity and regulating pluripotent state dynamics.