At the core of all small RNA pathways are the Argonaute (AGO) proteins, which interact with particular small RNA binding partners to regulate gene expression. C. elegans possesses 26 AGO family proteins and four types of endogenous small RNAs. Thus far, the characterization of a handful of AGOs in the worm has shown that they bind to non-overlapping subsets of small RNAs to perform distinct regulatory functions throughout development. However, a large number of the AGOs remain to be characterized, which could ultimately lead to novel insights into small RNA mediated gene regulatory functions. We have investigated the role that an uncharacterized, but well-conserved AGO, C04F12.1, plays in small RNA-mediated gene regulation throughout development. C04F12.1 is broadly expressed across most developmental stages and tissues, but is particularly enriched in the germline. Excitingly, C04F12.1 localizes to cytoplasmic germ granules (P granules) and to the nucleus, implicating C04F12.1 in both transcriptional and/or post-transcriptional gene regulation. To dissect the molecular functions of C04F12.1, we have cloned and Illumina sequenced small RNAs in both the C04F12.1(tm1637) mutant background and from C04F12.1 complexes. Remarkably, our analyses reveal that C04F12.1 associates with multiple classes of small RNAs, including a subset of miRNAs, piRNAs, and 22G-RNAs, whereas previously characterized worm AGOs generally associate with only one particular type of small RNA. Because of its unique capacity to associate with multiple small RNA classes, we have named C04F12.1 VSRA-1 (Versatile Small RNAs Argonaute-1). Consistent with functional roles utilizing multiple small RNA classes, vsra-1 displays synthetic genetic interactions with the AGOs generally associated with these categories of small RNAs (alg-1, prg-1, csr-1). In vivo reporter assays and mRNA-seq data indicate the functional importance of VSRA-1 and point to a role in silencing gene expression. These findings are exciting and point to a novel activity for the AGO VSRA-1 in multiple small RNA pathways. Further characterization of VSRA-1 will likely reveal new molecular mechanisms of AGO/small RNA-mediated gene regulation, including points of cross-talk and specificity between small RNA pathways. Furthermore, due to its unique property of being able to associate with multiple classes of small RNAs that generally possess different biochemical features, VSRA-1 can be exploited as a valuable tool in dissecting the requirements for small RNA loading onto particular AGO proteins in the worm.
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