Multiple Alternative Promoters and Alternative Splicing Enable Universal Transcription-Based Logic Computation in Mammalian Cells
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Date
2020
Publication Type
Journal Article
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yes
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Abstract
Multi-input logic gene circuits can enable sophisticated control of cell function, yet large-scale synthetic circuitry in mammalian cells has relied on post-transcriptional regulation or recombinase-triggered state transitions. Large-scale transcriptional logic, on the other hand, has been challenging to implement. Inspired by a naturally found regulatory strategy of using multiple alternative promoters, followed by alternative splicing, we developed a scalable and compact platform for transcriptional OR logic using inputs to those promoters. The platform is extended to implement disjunctive normal form (DNF) computations capable of implementing arbitrary logic rules. Specifically, AND logic is implemented at individual promoters using synergistic transcriptional inputs, and NOT logic via microRNA inputs targeting unique exon sequences driven by those promoters. Together, these regulatory programs result in DNF-like logic control of output gene expression. The approach offers flexibility for building complex logic programs in mammalian cells.
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published
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Journal / series
Volume
33 (9)
Pages / Article No.
108437
Publisher
Elsevier
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Software
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Organisational unit
03860 - Benenson, Yaakov (ehemalig) / Benenson, Yaakov (former)
03860 - Benenson, Yaakov (ehemalig) / Benenson, Yaakov (former)
Notes
Funding
175760 - Multi-input synthetic gene circuits: reduction to practice (SNF)