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Programming gene expression in multicellular organisms for physiology modulation through engineered bacteria.

ABSTRACT: A central goal of synthetic biology is to predictably and efficiently reprogram living systems to perform computations and carry out specific biological tasks. Although there have been many advances in the bio-computational design of living systems, these advances have mainly been applied to microorganisms or cell lines; programming animal physiology remains challenging for synthetic biology because of the system complexity. Here, we present a bacteria-animal symbiont system in which engineered bacteria recognize external signals and modulate animal gene expression, twitching phenotype, and fat metabolism through RNA interference toward gfp, sbp-1, and unc-22 gene in C. elegans. By using genetic circuits in bacteria to control these RNA expressions, we are able to program the physiology of the model animal Caenorhabditis elegans with logic gates. We anticipate that engineered bacteria can be used more extensively to program animal physiology for agricultural, therapeutic, and basic science applications.

SUBMITTER: Gao B

PROVIDER: S-EPMC8113242 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Programming gene expression in multicellular organisms for physiology modulation through engineered bacteria.

Gao Baizhen B Sun Qing Q

Nature communications 20210511 1

A central goal of synthetic biology is to predictably and efficiently reprogram living systems to perform computations and carry out specific biological tasks. Although there have been many advances in the bio-computational design of living systems, these advances have mainly been applied to microorganisms or cell lines; programming animal physiology remains challenging for synthetic biology because of the system complexity. Here, we present a bacteria-animal symbiont system in which engineered ...[more]

PMID: 33976154

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Project description:PurposeIn the programming of tumor-targeting bacteria, various therapeutic or reporter genes are expressed by different gene-triggering strategies. Previously, we engineered pJL87 plasmid with an inducible bacterial drug delivery system that simultaneously co-expressed two genes for therapy and imaging by a bidirectional tet promoter system only in response to the administration of exogenous doxycycline (Doxy). In this multi-cassette expression approach, tetA promoter (PtetA) was 100-fold higher in expression strength than tetR promoter (PtetR). In the present study, we developed pJH18 plasmid with novel Doxy-inducible gene expression system based on a tet promoter.ProceduresIn this system, Tet repressor (TetR) expressed by a weak constitutive promoter binds to tetO operator, resulting in the tight repression of gene expressions by PtetA and PtetR, and Doxy releases TetR from tetO to de-repress PtetA and PtetR.ResultsIn Salmonella transformed with pJH18, the expression balance of bidirectional tet promoters in pJH18 was remarkably improved (PtetA:PtetR = 4~6:1) compared with that of pJL87 (PtetA:PtetR = 100:1) in the presence of Doxy. Also, the expression level by novel tet system was much higher in Salmonella transformed with pJH18 than in those with pJL87 (80-fold in rluc8 and 5-fold in clyA). Interestingly, pJH18 of the transformed Salmonella was much more stably maintained than pJL87 in antibiotic-free tumor-bearing mice (about 41-fold), because only pJH18 carries bom sequence with an essential role in preventing the plasmid-free population of programmed Salmonella from undergoing cell division.ConclusionsOverall, doxycycline-induced co-expression of two proteins at similar expression levels, we exploited bioluminescence reporter proteins with preclinical but no clinical utility. Future validation with clinically compatible reporter systems, for example, suitable for radionuclide imaging, is necessary to develop this system further towards potential clinical application.

Dataset Information

Programming gene expression in multicellular organisms for physiology modulation through engineered bacteria.

Publications

Programming gene expression in multicellular organisms for physiology modulation through engineered bacteria.

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