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Dynamics and functional roles of splicing factor autoregulation

Fangyuan Ding, Christina Su, Ke-Huan Kuo Chow, Michael B. Elowitz
doi: https://doi.org/10.1101/2020.07.22.216887
Fangyuan Ding
1Division of Biology and Biological Engineering, Caltech, 1200 E. California Blvd. Pasadena, CA 91125, USA
2Howard Hughes Medical Institute
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Christina Su
1Division of Biology and Biological Engineering, Caltech, 1200 E. California Blvd. Pasadena, CA 91125, USA
2Howard Hughes Medical Institute
3David Geffen School of Medicine at UCLA, Los Angeles, CA 90095
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Ke-Huan Kuo Chow
1Division of Biology and Biological Engineering, Caltech, 1200 E. California Blvd. Pasadena, CA 91125, USA
2Howard Hughes Medical Institute
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Michael B. Elowitz
1Division of Biology and Biological Engineering, Caltech, 1200 E. California Blvd. Pasadena, CA 91125, USA
2Howard Hughes Medical Institute
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  • For correspondence: melowitz@caltech.edu
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Abstract

Non-spliceosomal splicing factors are essential, conserved regulators of alternative splicing. They provide concentration-dependent control of diverse pre-mRNAs. Many splicing factors direct unproductive splicing of their own pre-mRNAs through negative autoregulation. However, the impact of such feedback loops on splicing dynamics at the single cell level remains unclear. We developed a system to dynamically, quantitatively analyze negative autoregulatory splicing by the SF2 splicing factor in response to perturbations in single HEK293 cells. Here, we show that negative autoregulatory splicing provides critical functions for gene regulation, establishing a ceiling of SF2 protein concentration, reducing cell-cell heterogeneity in SF2 levels, and buffering variation in SF2 transcription. Most importantly, it adapts SF2 splicing activity to variations in demand from other pre-mRNA substrates. A minimal mathematical model of autoregulatory splicing explains these experimentally observed features, and provides values for effective biochemical parameters. These results reveal the unique functional roles that splicing negative autoregulation plays in homeostatically regulating transcriptional programs.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 24, 2020.
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Dynamics and functional roles of splicing factor autoregulation
Fangyuan Ding, Christina Su, Ke-Huan Kuo Chow, Michael B. Elowitz
bioRxiv 2020.07.22.216887; doi: https://doi.org/10.1101/2020.07.22.216887
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Dynamics and functional roles of splicing factor autoregulation
Fangyuan Ding, Christina Su, Ke-Huan Kuo Chow, Michael B. Elowitz
bioRxiv 2020.07.22.216887; doi: https://doi.org/10.1101/2020.07.22.216887

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