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Published June 2019 | Supplemental Material + Accepted Version + Submitted
Journal Article Open

Constitutive splicing and economies of scale in gene expression


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.

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.

Attached Files

Accepted Version - nihms-1033862.pdf

Submitted - 457432.full.pdf

Supplemental Material - 41594_2019_226_MOESM1_ESM.pdf

Supplemental Material - 41594_2019_226_MOESM2_ESM.pdf

Supplemental Material - 41594_2019_226_MOESM3_ESM.zip

Supplemental Material - 41594_2019_226_MOESM4_ESM.zip

Supplemental Material - 41594_2019_226_MOESM5_ESM.zip

Supplemental Material - 41594_2019_226_MOESM6_ESM.zip


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