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- W2753535118 abstract "Comprehensive de novo-design of complex mammalian promoters is restricted by unpredictable combinatorial interactions between constituent transcription factor regulatory elements (TFREs). In this study, we show that modular binding sites that do not function cooperatively can be identified by analyzing host cell transcription factor expression profiles, and subsequently testing cognate TFRE activities in varying homotypic and heterotypic promoter architectures. TFREs that displayed position-insensitive, additive function within a specific expression context could be rationally combined together in silico to create promoters with highly predictable activities. As TFRE order and spacing did not affect the performance of these TFRE-combinations, compositions could be specifically arranged to preclude the formation of undesirable sequence features. This facilitated simple in silico-design of promoters with context-required, user-defined functionalities. To demonstrate this, we de novo-created promoters for biopharmaceutical production in CHO cells that exhibited precisely designed activity dynamics and long-term expression-stability, without causing observable retroactive effects on cellular performance. The design process described can be utilized for applications requiring context-responsive, customizable promoter function, particularly where co-expression of synthetic TFs is not suitable. Although the synthetic promoter structure utilized does not closely resemble native mammalian architectures, our findings also provide additional support for a flexible billboard model of promoter regulation." @default.
- W2753535118 created "2017-09-15" @default.
- W2753535118 creator A5000736115 @default.
- W2753535118 creator A5022494700 @default.
- W2753535118 creator A5045290531 @default.
- W2753535118 creator A5063523432 @default.
- W2753535118 date "2017-08-30" @default.
- W2753535118 modified "2023-10-17" @default.
- W2753535118 title "In silico design of context-responsive mammalian promoters with user-defined functionality" @default.
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- W2753535118 doi "https://doi.org/10.1093/nar/gkx768" @default.
- W2753535118 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5737543" @default.
- W2753535118 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/28977454" @default.
- W2753535118 hasPublicationYear "2017" @default.
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