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PreprintCited by 4RNA 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

Open access
Knudsen-Palmer, Daphne R., Raman, Pravrutha, Ettefa, Farida, De Ravin, Laura, Jose, Antony M.·2023·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2023.02.07.527351PMC PMC9934570

Preprint — published as 10.7554/elife.97487 · Paper page

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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 C. 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, is 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, College Park (US)
  • Fred Hutch Cancer Center (US)
  • New York University (US)
Corresponding author
Jose, Antony M.
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2023-02-08
DOI
10.1101/2023.02.07.527351
PMC
PMC9934570
OpenAlex
W4319592712
Cited by
4
References
1
Citations by year
2025: 1 · 2024: 2 · 2023: 1
Type
posted content
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • National Science Foundation (2120895)
  • National Institutes of Health
  • National Institute of General Medical Sciences (R01GM111457, R01GM124356)
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, gene silencing, double-stranded RNA, Argonaute proteins, RNA amplification, small RNA, cis-regulatory elements, Caenorhabditis elegans

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