Sequential TPRX1 and HERVL activation delineates a progression toward the totipotent-like state.

Sequential activation of TPRX1 and HERVL defines the stepwise progression toward human 8-cell-like cells in vitro.

• Why it matters: Understanding the cellular dynamics of totipotency and zygotic genome activation (ZGA) is crucial for insights into early human development, yet remains poorly understood.
• What they did: A dual-reporter human pluripotent stem cell line was generated to track TPRX1 and HERVL activation, revealing an ordered trajectory from primed cells through TPRX1 + intermediates to HERVL + 8CLCs, supported by single-cell transcriptomics and perturbation experiments.
• The result: Sequential TPRX1 and HERVL activation is established as a key feature of human 8CLC induction, with HERVL elements and RNA contributing functionally to this transition, advancing understanding of totipotent-like state acquisition.