A new study has found that L1td1, a protein evolutionarily co-opted from the Long interspersed nuclear element 1 (LINE1) retrotransposon, functions as a critical "gatekeeper" restricting pluripotent stem cells (PSCs) from reverting to a totipotent state.
The research demonstrates that loss of L1td1 triggers the reactivation of totipotency-associated genes and endogenous retroviruses (ERVs), prompting cells to spontaneously regress to a totipotent-like (or 2-cell-like) state that mirrors the earliest stages of embryogenesis. Notably, the study identifies L1td1 as a key post-transcriptional regulator that suppresses endogenous viral elements to sustain pluripotency.
Led by Prof. LIU Xinguo from the Guangzhou Institutes of Biomedicine and Health (GIBH) of the Chinese Academy of Sciences, the study was recently published in Cell Discovery.
The transition from totipotency to pluripotency is a fundamental event in early embryonic development, marked by the silencing of totipotent genes and specific retrotransposons activated during zygotic genome activation (ZGA). While transcriptional and epigenetic mechanisms governing this developmental restriction have been extensively investigated, the role of post-transcriptional regulation-particularly RNA decay-has remained poorly understood.
L1td1 is the only mammalian protein-coding gene domesticated from the "jumping" LINE-1 retrotransposon and is highly expressed in PSCs. However, its precise function in regulating cell fate transitions had remained unclear prior to this research.
To address this knowledge gap, the research team employed mouse and human PSC models and uncovered that L1td1 plays a decisive role in preventing the acquisition of totipotency. Mechanistically, L1td1 recruits the CCR4-NOT deadenylase complex to specifically target and degrade RNA transcripts essential for totipotency, including the Zscan4 gene family and ERVs such as MERVL-int and MT2_Mm.
Notably, the study also found that L1td1 targets the RNA of its own evolutionary progenitor-LINE-1-for degradation. By clearing these transcripts, L1td1 effectively blocks reversion to a 2-cell-like (2C-like) state, thereby preserving the pluripotent identity of the cell.
This study reveals a new mechanism: a co-opted transposon protein utilizes the CCR4-NOT machinery to link transposon silencing with cell fate determination. It also underscores the importance of RNA stability control in early embryonic development and genome defense.
These findings provide new theoretical insights into the evolutionary interplay between viral elements and host developmental regulation, offering potential strategies for inducing totipotency in regenerative medicine and xenogeneic organ regeneration.
The study was supported by the National Key R&D Program of China, the National Natural Science Foundation of China, and other funding sources.
