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

Authors

An Huang, Nan Jiang, Sen Luo, Xi Kong, Simeng Yi, Shigang Yin, Jianhua Peng, Yong Jiang, Huangfan Xie, Bingqing Xie

Published in

Cell reports. Volume 45. Issue 11. Pages 118163. Oct 17, 2026. Epub Oct 17, 2026.

Abstract

The in vitro induction of 8-cell-like cells (8CLCs) from human pluripotent stem cells (hPSCs) provides a model to study the regulatory principles of totipotency and zygotic genome activation (ZGA). However, the cellular dynamics underlying 8CLC emergence remain poorly understood. Here, we generate a TPRX1-EGFP/HERVL-tdTomato dual-reporter hPSC line to resolve the stepwise acquisition of totipotent-like identity. We show that 8CLC induction follows an ordered trajectory in which TPRX1 activation precedes the emergence of TPRX1⁺HERVL⁺ cells, which most closely resemble the in vivo 8-cell embryo transcriptionally. Single-cell transcriptomics and time-resolved flow cytometry further define a continuous transition from the primed state through a TPRX1⁺ intermediate to the HERVL⁺ 8CLC state. CRISPRi and RNA-directed perturbations support functional contributions of HERVL elements and HERVL-derived RNA to this transition, while potential locus-dependent mechanisms remain unresolved. Together, these findings establish sequential TPRX1 and HERVL activation as a defining feature of human 8CLC induction.

PMID:
42893511
Bibliographic data and abstract were imported from PubMed on 19 Oct 2026.

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