Cellular quiescence uncouples the proteome from the transcriptome in neural stem cells

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Alice Rossi Antoine Coum Manon Madelenat Lachlan Harris Stephanie Strohbuecker Andrea Chai Hania Fiaz Rita Chaouni Peter Faull Neve Costello Heaven William Grey Dominique Bonnet Fursham Hamid Eugene V Makeyev Bram Snijders Gavin Kelly Francois Guillemot Rita Sousa-Nunes
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Abstract

Quiescence is a cellular state defined by reversible cell-cycle arrest and diminished biosynthesis, particularly of nucleic acids and proteins. These features protect stem cells from proliferation-induced mutations, self-renewal exhaustion, and environmental insults. Despite relevance to development, tissue homeostasis and cancer, we lack understanding about many aspects of quiescence regulation and unique molecular markers for this state. Here, we employ Drosophila and mammalian neural stem cells to reveal that a mechanism for inhibiting translation in quiescence is selective nuclear enrichment of transcripts from more than 2000 genes, resulting in uncoupling between transcriptome and proteome. Three-quarters of these transcripts become increasingly nuclear as quiescence deepens, and nuclear bias predicts protein downregulation for the large majority of targets. We find that a large fraction of nuclear-biased transcripts present GA-rich multivalency and relocalise to nuclear speckles with increased SR-protein enrichment, which we propose promotes their nuclear retention. Finally, our evidence for differing degrees of transcript processing in steady-state quiescence suggests regulated sequential deployment of factors towards cell-cycle reentry. In brief, we present a previously unappreciated layer of post-transcriptional control of quiescence.

Journal details

Journal EMBO Journal
Volume 45
Issue number 5
Pages 1697-1727
Available online
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Publisher website (DOI) 10.1038/s44318-026-00693-4
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Europe PubMed Central 41645004
Pubmed 41645004

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The publication was previously a preprint. View preprint