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Constitutive splicing and economies of scale in gene expression

Ding, Fangyuan and Elowitz, Michael B. (2019) Constitutive splicing and economies of scale in gene expression. Nature Structural & Molecular Biology, 26 (6). pp. 424-432. ISSN 1545-9985. PMCID PMC6663491.

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In eukaryotic cells, many introns are constitutively, rather than alternatively, spliced and therefore do not contribute to isoform diversification. It has remained unclear what functional roles such constitutive splicing provides. To explore this issue, we asked how splicing affects the efficiency with which individual pre-messenger RNA transcripts are productively processed across different gene expression levels. We developed a quantitative single-molecule fluorescence in situ hybridization-based method to quantify splicing efficiency at transcription active sites in single cells. We found that both natural and synthetic genes in mouse and human cells exhibited an unexpected ‘economy of scale’ behavior in which splicing efficiency increased with transcription rate. Correlations between splicing efficiency and spatial proximity to nuclear speckles could explain this counterintuitive behavior. Functionally, economy of scale splicing represents a non-linear filter that amplifies the expression of genes when they are more strongly transcribed. These results indicate that constitutive splicing plays an active functional role in modulating gene expression.

Item Type:Article
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URLURL TypeDescription ReadCube access CentralArticle Paper
Ding, Fangyuan0000-0003-0118-5441
Elowitz, Michael B.0000-0002-1221-0967
Alternate Title:Quantitative single-cell splicing analysis reveals an 'economy of scale' filter for gene expression
Additional Information:© 2019 Nature Publishing Group. Received 27 November 2018; Accepted 11 April 2019; Published 27 May 2019. Data availability: Source data for Figs. 2, 3d,e, 4 and 5d are available online. All other original data, Matlab code, DNA constructs and cell lines are available upon request. We thank T. Cooper for DNA constructs of minigene RG6, P. Li for providing Gli1 inducible protocol, Z. Singer and Y. Antebi for technical assistance, M. Guttman, C. Su, H. Klumpe, M. Budde and L. Bintu for critical feedbacks on the manuscript. We also thank M. Guttman, G. Seelig, D. Black, D. Baltimore, M. Moore, J.G. Ojalvo and N. Wingreen for discussion and feedback on the project. The work was funded by a Fellowship from the Schlumberger Foundation, by the Gordon and Betty Moore Foundation through Grant GBMF2809 to the Caltech Programmable Molecular Technology Initiative and the Institute for Collaborative Biotechnologies through grant W911NF-09-0001 from the U.S. Army Research Office. The content of the information does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred. M.B.E. is a Howard Hughes Medical Institute Investigator. Author Contributions: F.D. conceived of the project. F.D. and M.B.E. designed experiments. F.D. performed experiments, analyzed data and did mathematical modeling. F.D. and M.B.E. wrote the manuscript. The authors declare no competing interests.
Funding AgencyGrant Number
Schlumberger FoundationUNSPECIFIED
Gordon and Betty Moore FoundationGBMF2809
Army Research Office (ARO)W911NF-09-0001
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:Cellular imaging; Fluorescence in situ hybridization; RNA splicing
Issue or Number:6
PubMed Central ID:PMC6663491
Record Number:CaltechAUTHORS:20181107-102333115
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Official Citation:Ding, F., Elowitz, M.B. Constitutive splicing and economies of scale in gene expression. Nat Struct Mol Biol 26, 424–432 (2019).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90703
Deposited By: Tony Diaz
Deposited On:07 Nov 2018 19:24
Last Modified:10 Dec 2020 19:32

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