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Two parallel sRNA amplification cycles contribute to RNAi inheritance in C. elegans

View ORCID ProfileJohn Paul Tsu Ouyang, Wenyan Zhang, View ORCID ProfileGeraldine Seydoux
doi: https://doi.org/10.1101/2021.08.13.456232
John Paul Tsu Ouyang
1HHMI and Dept. of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore MD USA
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Wenyan Zhang
1HHMI and Dept. of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore MD USA
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Geraldine Seydoux
1HHMI and Dept. of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore MD USA
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  • ORCID record for Geraldine Seydoux
  • For correspondence: gseydoux@jhmi.edu
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Abstract

RNA-mediated interference (RNAi) is a conserved mechanism that uses small RNAs (sRNAs) to tune gene expression. In C. elegans, exposure to dsRNA induces the production of gene-specific sRNAs that are propagated to progeny not exposed to the dsRNA trigger. We present evidence that RNAi inheritance is mediated by two parallel sRNA amplification loops. The first loop, dependent on the nuclear Argonaute HRDE-1, targets nascent transcripts, and reduces but does not eliminate productive transcription at the locus. The second loop, dependent on the conserved helicase ZNFX-1, targets mature transcripts and concentrates them in perinuclear condensates (nuage). Each amplification loop generates a distinct class of sRNAs, with the ZNFX-1 loop responsible for the bulk of sRNA production on the region targeted by the trigger. By independently targeting nascent and mature transcripts, the HRDE-1 and ZNFX-1 loops ensure maximum silencing in progeny not exposed to the trigger.

Competing Interest Statement

G.S. serves on the Scientific Advisory Board of Dewpoint Therapeutics, Inc.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 13, 2021.
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Two parallel sRNA amplification cycles contribute to RNAi inheritance in C. elegans
John Paul Tsu Ouyang, Wenyan Zhang, Geraldine Seydoux
bioRxiv 2021.08.13.456232; doi: https://doi.org/10.1101/2021.08.13.456232
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Two parallel sRNA amplification cycles contribute to RNAi inheritance in C. elegans
John Paul Tsu Ouyang, Wenyan Zhang, Geraldine Seydoux
bioRxiv 2021.08.13.456232; doi: https://doi.org/10.1101/2021.08.13.456232

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