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Cited by 2RNA Interference and Gene DeliveryRNA Research and SplicingRNA regulation and disease

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Target-specific requirements for RNA interference can arise through restricted RNA amplification despite the lack of specialized pathways

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Knudsen-Palmer, Daphne R, Raman, Pravrutha, Ettefa, Farida, De Ravin, Laura, Jose, Antony M·2024·eLife
DOI 10.7554/elife.97487.3

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Abstract

Since double-stranded RNA (dsRNA) is effective for silencing a wide variety of genes, all genes are typically considered equivalent targets for such RNA interference (RNAi). Yet, loss of some regulators of RNAi in the nematode Caenorhabditis elegans can selectively impair the silencing of some genes. Here, we show that such selective requirements can be explained by an intersecting network of regulators acting on genes with differences in their RNA metabolism. In this network, the Maelstrom domain-containing protein RDE-10, the intrinsically disordered protein MUT-16, and the Argonaute protein NRDE-3 work together so that any two are required for silencing one somatic gene, but each is singly required for silencing another somatic gene, where only the requirement for NRDE-3 can be overcome by enhanced dsRNA processing. Quantitative models and their exploratory simulations led us to find that (1) changing cis -regulatory elements of the target gene can reduce the dependence on NRDE-3, (2) animals can recover from silencing in non-dividing cells, and (3) cleavage and tailing of mRNAs with UG dinucleotides, which makes them templates for amplifying small RNAs, are enriched within ‘pUG zones’ matching the dsRNA. Similar crosstalk between pathways and restricted amplification could result in apparently selective silencing by endogenous RNAs.

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Metadata

Authors
Knudsen-Palmer, D. R., Raman, P., Ettefa, F., De Ravin, L., & Jose, A. M.
Affiliations
  • University of Maryland, Baltimore (US)
  • Department of Cell Biology and Molecular Genetics, Biological Sciences Graduate Program, University of Maryland
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-08-20
Volume
13
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.97487.3
OpenAlex
W4401973237
Cited by
2
References
1
Citations by year
2026: 1 · 2025: 1
FWCI
0.27
Type
journal article
Language
en
Open access
Licence
Locations
eLife (publishedVersion, cc-by)
Funders
  • National Institutes of Health (R01GM111457, R01GM124356)
  • National Science Foundation (2120895)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords
RNA interference, Caenorhabditis elegans, gene silencing, Argonaute proteins, cis-regulatory elements, non-dividing cells

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