Genome-wide quantification of RNA flow across subcellular compartments reveals determinants of the mammalian transcript life cycle
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Abstract
Dissecting the regulatory mechanisms controlling mammalian 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 in human and mouse cells. 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 a link between DDX3X and nuclear export. For hundreds of RNA metabolism genes, most transcripts with retained introns were degraded by the nuclear exosome, while the remaining molecules were exported with stable cytoplasmic lifespans. Transcripts residing on chromatin for longer had extended poly(A) tails, whereas the reverse was observed for cytoplasmic mRNAs. Finally, machine learning identified molecular features that predicted the diverse life cycles of mRNAs.
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- Authors
- Ietswaart, R., Smalec, B. M., Xu, A., Choquet, K., McShane, E., Jowhar, Z. M., Guegler, C. K., Baxter-Koenigs, A. R., West, E. R., Fu, B. X. H., Gilbert, L., Floor, S. N., & Churchman, L. S.
- Affiliations
- Harvard University (US)
- University of California, San Francisco (US)
- Arc Research Institute (US)
- Corresponding author
- Ietswaart, Robert
- Floor, Stephen N.
- Churchman, L. Stirling
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2024-07
- Volume
- 84
- Issue
- 14
- Pages
- 2765-2784.e16
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC11315470
- OpenAlex
- W4400281042
- Cited by
- 83
- References
- 13
- Citations by year
- 2026: 16 · 2025: 33 · 2024: 17 · 2023: 16 · 2020: 1
- FWCI
- 8.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 389 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation (DGE-1745303, T32GM007748, F30HD110250)
- Canadian Institutes of Health Research
- Pew Charitable Trusts
- National Institutes of Health (T32GM007748, R21HG011682, R01NS120667, R01HG007173)
- Fonds de Recherche du Québec - Santé
- Jane Coffin Childs Memorial Fund for Medical Research
- University of California, San Francisco
- 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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