UMMS Affiliation

RNA Therapeutics Institute; Graduate School of Biomedical Sciences

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Developmental Biology | Genetics and Genomics | Nucleic Acids, Nucleotides, and Nucleosides


In animals, Argonaute small-RNA pathways scan germline transcripts to silence self-replicating genetic elements. However, little is known about how endogenous gene expression is recognized and licensed. Here, we show that the presence of introns and, by inference, the process of mRNA splicing prevents default Argonaute-mediated silencing in the C. elegans germline. The silencing of intronless genes is initiated independently of the piRNA pathway but nevertheless engages multiple components of the downstream amplification and maintenance mechanisms that mediate transgenerational silencing, including both nuclear and cytoplasmic members of the worm-specific Argonaute gene family (WAGOs). Small RNAs amplified from intronless mRNAs can trans-silence cognate intron-containing genes. Interestingly, a second, small RNA-independent cis-acting mode of silencing also acts on intronless mRNAs. Our findings suggest that cues put in place during mRNA splicing license germline gene expression and provide evidence for a splicing-dependent and dsRNA- and piRNA-independent mechanism that can program Argonaute silencing.


C. elegans, RNA processing, RNA splicing, RNAi, epigenetic inheritance, gene expression surveillance, intronless genes, piRNA

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Copyright 2021 The Authors. This is an open access article under the CC BY-NC-ND license (

DOI of Published Version



Makeyeva YV, Shirayama M, Mello CC. Cues from mRNA splicing prevent default Argonaute silencing in C. elegans. Dev Cell. 2021 Sep 27;56(18):2636-2648.e4. doi: 10.1016/j.devcel.2021.08.022. Epub 2021 Sep 20. PMID: 34547227; PMCID: PMC8693449. Link to article on publisher's site

Journal/Book/Conference Title

Developmental cell

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Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.