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PreprintCited by 83RNA Research and SplicingRNA and protein synthesis mechanismsGenomics and Chromatin Dynamics

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Genome-wide quantification of RNA flow across subcellular compartments reveals determinants of the mammalian transcript life cycle

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Smalec, Brendan M., Ietswaart, Robert, Choquet, Karine, McShane, Erik, West, Emma R., Churchman, L. Stirling·2022·Molecular Cell
DOI 10.1101/2022.08.21.504696PMC PMC11315470

Preprint — published as 10.1016/j.molcel.2024.06.008 · Paper page

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Abstract

Dissecting the myriad regulatory mechanisms controlling eukaryotic transcripts from production to degradation requires quantitative measurements of mRNA flow across the cell. We developed subcellular TimeLapse-seq to measure the rates at which RNAs are released from chromatin, exported from the nucleus, loaded onto polysomes, and degraded within the nucleus and cytoplasm. These rates varied substantially, yet transcripts from genes with related functions or targeted by the same transcription factors and RNA binding proteins flowed across subcellular compartments with similar kinetics. Verifying these associations uncovered roles for DDX3X and PABPC4 in nuclear export. For hundreds of genes, most transcripts were degraded within the nucleus, while the remaining molecules were exported and persisted with stable lifespans. Transcripts residing on chromatin for longer had extended poly(A) tails, whereas the reverse was observed for cytoplasmic mRNAs. Finally, a machine learning model identified additional molecular features that underlie the diverse life cycles of mammalian mRNAs.

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Metadata

Authors
Smalec, B. M., Ietswaart, R., Choquet, K., McShane, E., West, E. R., & Churchman, L. S.
Affiliations
Harvard University (US)
Corresponding author
  • Ietswaart, Robert
  • Churchman, L. Stirling
ORCID
Venue
Molecular Cell
Publisher
openRxiv
Published
2022-08-21
Volume
84
Issue
14
Pages
2765-2784.e16
ISSN
1097-2765 (ISSN-L)
DOI
10.1101/2022.08.21.504696
PMC
PMC11315470
OpenAlex
W4400281042
Cited by
83
References
1
Citations by year
2026: 16 · 2025: 33 · 2024: 17 · 2023: 16
FWCI
8.98
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Science Foundation (F30HD110250, 1745303, T32GM007748)
  • Pew Charitable Trusts
  • Jane Coffin Childs Memorial Fund for Medical Research
  • Boston Children's Hospital
  • Harvard University
  • National Institutes of Health (1r21hg011682-01a1)
  • University of California, San Francisco
  • Canadian Institutes of Health Research
  • Fonds de Recherche du Québec - Santé
  • National Human Genome Research Institute (R21 HG011682, R01HG007173)
  • National Institute of General Medical Sciences (T32GM007748)
  • National Institute of Neurological Disorders and Stroke (R01NS120667)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (F30HD110250)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
nuclear export, mRNA degradation, nuclear exosome, poly(A) tail length, DDX3X, RNA-binding proteins, transcription factors, intron retention, transcript stability
MeSH terms
Machine Learning, Animals, Cell Nucleus, Chromatin, Cytoplasm, Humans, Polyribosomes, RNA, Messenger, RNA-Binding Proteins, RNA Stability, Active Transport, Cell Nucleus, Mice, DEAD-box RNA Helicases, Exosomes

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