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Feedback from nuclear RNA on transcription promotes robust RNA concentration homeostasis in human cells


Berry, Scott; Müller, Micha; Rai, Arpan; Pelkmans, Lucas (2022). Feedback from nuclear RNA on transcription promotes robust RNA concentration homeostasis in human cells. Cell Systems, 13(6):454-470.e15.

Abstract

RNA concentration homeostasis involves coordinating RNA abundance and synthesis rates with cell size. Here, we study this in human cells by combining genome-wide perturbations with quantitative single-cell measurements. Despite relative ease in perturbing RNA synthesis, we find that RNA concentrations generally remain highly constant. Perturbations that would be expected to increase nuclear mRNA levels, including those targeting nuclear mRNA degradation or export, result in downregulation of RNA synthesis. This is associated with reduced abundance of transcription-associated proteins and protein states that are normally coordinated with RNA production in single cells, including RNA polymerase II (RNA Pol II) itself. Acute perturbations, elevation of nuclear mRNA levels, and mathematical modeling indicate that mammalian cells achieve robust mRNA concentration homeostasis by the mRNA-based negative feedback on transcriptional activity in the nucleus. This ultimately acts to coordinate RNA Pol II abundance with nuclear mRNA degradation and export rates and may underpin the scaling of mRNA abundance with cell size.

Keywords: RNA metabolism; cell size scaling; homeostasis; ribostasis; transcription.

Abstract

RNA concentration homeostasis involves coordinating RNA abundance and synthesis rates with cell size. Here, we study this in human cells by combining genome-wide perturbations with quantitative single-cell measurements. Despite relative ease in perturbing RNA synthesis, we find that RNA concentrations generally remain highly constant. Perturbations that would be expected to increase nuclear mRNA levels, including those targeting nuclear mRNA degradation or export, result in downregulation of RNA synthesis. This is associated with reduced abundance of transcription-associated proteins and protein states that are normally coordinated with RNA production in single cells, including RNA polymerase II (RNA Pol II) itself. Acute perturbations, elevation of nuclear mRNA levels, and mathematical modeling indicate that mammalian cells achieve robust mRNA concentration homeostasis by the mRNA-based negative feedback on transcriptional activity in the nucleus. This ultimately acts to coordinate RNA Pol II abundance with nuclear mRNA degradation and export rates and may underpin the scaling of mRNA abundance with cell size.

Keywords: RNA metabolism; cell size scaling; homeostasis; ribostasis; transcription.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Health Sciences > Pathology and Forensic Medicine
Health Sciences > Histology
Life Sciences > Cell Biology
Uncontrolled Keywords:Cell Biology, Histology, Pathology and Forensic Medicine
Language:English
Date:1 June 2022
Deposited On:01 Sep 2022 08:32
Last Modified:27 Jun 2024 01:39
Publisher:Cell Press (Elsevier)
ISSN:2405-4712
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.cels.2022.04.005
Related URLs:https://www.sciencedirect.com/science/article/abs/pii/S2405471222001703?via%3Dihub%3C/official_url (Publisher)
PubMed ID:35613616
Project Information:
  • : FunderEuropean Research Council
  • : Grant ID
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  • : FunderSNSF
  • : Grant ID310030_192622
  • : Project TitleMolecular mechanisms of DYRK3-controlled intracellular phase separation
  • : FunderUniversity of New South Wales
  • : Grant ID
  • : Project Title
  • : FunderUniversität Zürich
  • : Grant ID
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