Endo-siRNAs are an evolutionarily conserved class of small RNAs present across eukaryotes and particularly enriched in oocytes and early embryos, where they constitute the most abundant small RNA population¹. Previous work reported that the disruption of endo-siRNA pathways leads to complete embryonic arrest after fertilization². Despite these profound phenotypes, the molecular mechanisms underlying endo-siRNA function during reproduction have remained unresolved.
Despite extensive efforts to catalog small RNA populations in germ cells, identifying the direct slicing targets of endogenous siRNAs in oocytes has remained technically challenging. Here, Shen’s team at Westlake University overcame this barrier by applying optimized degradome sequencing to detect Argonaute-mediated slicing events in germ cells, providing the first comprehensive identification of direct cleavage targets of AGO2/endo-siRNAs in mouse oocytes. They show that, among the identified endo-siRNA targets, genes encoding proteasome subunits emerge as a prominent category. The proteasome is the central machinery for intracellular protein degradation, and its activity is tightly linked to cellular metabolism and turnover³. In oocytes, the accumulation of maternal components and their essential roles in early embryogenesis necessitate precise regulation of proteasome activity. By directing the slicing of key proteasome subunit transcripts, endo-siRNAs limit proteasome assembly, reduce proteasome activity, and thereby preserve maternal ribosomes. This study thus establishes a critical physiological function of endo-siRNAs in supporting zygotic genome activation and early embryonic development.
An important conceptual implication of this work lies in the origin of mammalian endo-siRNAs. Shen’s team reveals that in mouse oocytes, endo-siRNAs are largely derived from transposon sequences, which are mobile genetic elements capable of copying or moving within the genome^1,4. Transposon expression can disrupt genome integrity by inducing insertional mutagenesis and genomic instability⁵. As a result, transposons have been viewed as deleterious elements—often labeled as genomic “junk”—that commonly be repressed in somatic cells⁶. In contrary, oocytes exhibit a distinctive environment in which transposons are actively expressed¹. They demonstrate that the roles of these transposon-derived siRNAs are not only restricted to transposon silencing, but play an essential physiological role by restraining proteasome activity and thereby safeguarding the maternal proteome. This finding reframes transposons not as passive genomic burdens but as sources of regulatory small RNAs that enable precise control of proteasome activity during a critical reproductive developmental window.
Moreover, the regulatory framework uncovered in mice resonates with prior observations in C. elegans, where loss of the Argonaute CSR-1 and its associated 22G siRNAs results in complete sterility and embryonic lethality^7,8. Although small RNA biogenesis pathways differ substantially between nematodes and mammals, They find that both CSR-1-associated 22G RNAs in worms and AGO2–endo-siRNAs in mouse oocytes converge on a shared principle: Argonaute–small RNA pathways actively restrain proteasome function and preserve the ribosome proteins in germ cells. These findings highlight an evolutionary flexibility built upon a conserved functional imperative to protect the maternal translation machinery from untimely degradation.
This study repositions endo-siRNAs as novel and conserved regulators of the protein degradation system during maternal-to-zygote transition, ensuring the degradation fidelity in oocytes and safeguarding the generational continuity. Building on these findings, many additional physiological functions of small RNAs during embryonic development remain to be uncovered. Moreover, similar regulatory strategies employed by distinct classes of small RNAs may operate in the reproductive processes of other species (Fig.1). This work opens a new avenue for exploring the roles of small RNAs at the onset of life.
DOI：10.15302/vita.2026.02.0012