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Example of a genetic regulatory circuit for Drosophila melanogaster's huckebein (hkb) gene's effects on gap gene expression.

Discovery and definition

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Genetic regulatory circuits (also referred to as transcriptional regulatory circuits) is a concept that evolved from the Operon Model discovered by François Jacob and Jacques Monod [1] [2][3]. They are functional clusters of genes that impact each other's expression through inducible transcription factors and cis-regulatory elements [4] [5] .

Genetic regulatory circuits are analogous in many ways to electronic circuits in how they use signal inputs and outputs to determine gene regulation[4] [6] . Like electronic circuits, their organization determines their efficiency, and this has been demonstrated in circuits working in series to have a greater sensitivity of gene regulation[4] [7]. They also use inputs such as trans and cis sequence regulators of genes, and outputs such as gene expression level[4] [5]. Depending on the type of circuit, they respond constantly to outside signals, such as sugars and hormone levels, that determine how the circuit will return to its fixed point or periodic equilibrium state[8]. Genetic regulatory circuits also have an ability to be evolutionarily rewired without the loss of the original transcriptional output level[9] [10]. This rewiring is defined by the change in regulatory-target gene interactions, while there is still conservation of regulatory factors and target genes[9][11].

In-silico application

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These circuits can be modelled in silico to predict the dynamics of a genetic system[9] [12]. Having constructed a computational model of the natural circuit of interest, one can use the model to make testable predictions about circuit performance[13] [14]. When designing a synthetic circuit for a specific engineering task, a model is useful for identifying necessary connections and parameter operating regimes that give rise to a desired functional output. Similarly, when studying a natural circuit, one can use the model to identify the parts or parameter values necessary for a desired biological outcome[13] [15] In other words, computational modelling and experimental synthetic perturbations can be used to probe biological circuits[13] [15]. However, the structure of the circuits have shown to not be a reliable indicator of the function that the regulatory circuit provides for the larger cellular regulatory network[8].

Engineering and synthetic biology

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Understanding of genetic regulatory circuits are key in the field of synthetic biology, where disparate genetic elements are combined to produce novel biological functions [1][13]. These biological gene circuits can be used synthetically to act as physical models for studying regulatory function [16] [17] .

By engineering genetic regulatory circuits, cells can be modified to take information from their environment, such as nutrient availability and developmental signals, and react in accordance to changes in their surroundings [18] [19][20][21]. In plant synthetic biology, genetic regulatory circuits can be used to program traits to increase crop plant efficiency by increasing their robustness to environmental stressors [19][22]. Additionally, they are used to produce biopharmaceuticals for medical intervention [19][22].

  1. ^ a b "Integrated Gene Regulatory Circuits: Celebrating the 50th Anniversary of the Operon Model". Molecular Cell. 43 (4): 505–514. 2011-08-19. doi:10.1016/j.molcel.2011.08.003. ISSN 1097-2765.
  2. ^ Kelly, Daniel P.; Scarpulla, Richard C. (2004-02-15). "Transcriptional regulatory circuits controlling mitochondrial biogenesis and function". Genes & Development. 18 (4): 357–368. doi:10.1101/gad.1177604. ISSN 0890-9369. PMID 15004004.
  3. ^ Jacob, François; Monod, Jacques (1961-06-01). "Genetic regulatory mechanisms in the synthesis of proteins". Journal of Molecular Biology. 3 (3): 318–356. doi:10.1016/S0022-2836(61)80072-7. ISSN 0022-2836.
  4. ^ a b c d Kim, Harold D.; Shay, Tal; O'Shea, Erin K.; Regev, Aviv (2009-07-24). "Transcriptional Regulatory Circuits: Predicting Numbers from Alphabets". Science (New York, N.Y.). 325 (5939): 429–432. doi:10.1126/science.1171347. ISSN 0036-8075. PMC 2745280. PMID 19628860.
  5. ^ a b Bintu, Lacramioara; Buchler, Nicolas E.; Garcia, Hernan G.; Gerland, Ulrich; Hwa, Terence; Kondev, Jané; Kuhlman, Thomas; Phillips, Rob (2005-04). "Transcriptional regulation by the numbers: applications". Current Opinion in Genetics & Development. 15 (2): 125–135. doi:10.1016/j.gde.2005.02.006. ISSN 0959-437X. PMC 3462814. PMID 15797195. {{cite journal}}: Check date values in: |date= (help)
  6. ^ Mortazavi, Ali; Williams, Brian A.; McCue, Kenneth; Schaeffer, Lorian; Wold, Barbara (2008-07). "Mapping and quantifying mammalian transcriptomes by RNA-Seq". Nature Methods. 5 (7): 621–628. doi:10.1038/nmeth.1226. ISSN 1548-7105. PMID 18516045. {{cite journal}}: Check date values in: |date= (help)
  7. ^ Hooshangi, Sara; Thiberge, Stephan; Weiss, Ron (2005-03-08). "Ultrasensitivity and noise propagation in a synthetic transcriptional cascade". Proceedings of the National Academy of Sciences of the United States of America. 102 (10): 3581–3586. doi:10.1073/pnas.0408507102. ISSN 0027-8424. PMID 15738412.
  8. ^ a b Payne, Joshua L.; Wagner, Andreas (2015-08-20). "Function does not follow form in gene regulatory circuits". Scientific Reports. 5 (1): 13015. doi:10.1038/srep13015. ISSN 2045-2322.
  9. ^ a b c Dalal, Chiraj K.; Johnson, Alexander D. (2017-07-15). "How transcription circuits explore alternative architectures while maintaining overall circuit output". Genes & Development. 31 (14): 1397–1405. doi:10.1101/gad.303362.117. ISSN 0890-9369. PMID 28860157.
  10. ^ Hare, Emily E.; Peterson, Brant K.; Iyer, Venky N.; Meier, Rudolf; Eisen, Michael B. (2008-06-27). "Sepsid even-skipped Enhancers Are Functionally Conserved in Drosophila Despite Lack of Sequence Conservation". PLOS Genetics. 4 (6): e1000106. doi:10.1371/journal.pgen.1000106. ISSN 1553-7404. PMC 2430619. PMID 18584029.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  11. ^ Martchenko, Mikhail; Levitin, Anastasia; Hogues, Herve; Nantel, Andre; Whiteway, Malcolm (2007-06-19). "Transcriptional rewiring of fungal galactose-metabolism circuitry". Current biology: CB. 17 (12): 1007–1013. doi:10.1016/j.cub.2007.05.017. ISSN 0960-9822. PMC 3842258. PMID 17540568.
  12. ^ Ciliberti, Stefano; Martin, Olivier C.; Wagner, Andreas (2007-02-02). "Robustness Can Evolve Gradually in Complex Regulatory Gene Networks with Varying Topology". PLOS Computational Biology. 3 (2): e15. doi:10.1371/journal.pcbi.0030015. ISSN 1553-7358. PMC 1794322. PMID 17274682.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  13. ^ a b c d Porter, Joshua R.; Batchelor, Eric (2015). "Using Computational Modeling and Experimental Synthetic Perturbations to Probe Biological Circuits". Methods in molecular biology (Clifton, N.J.). 1244: 259–276. doi:10.1007/978-1-4939-1878-2_12. ISSN 1064-3745. PMC 6311997. PMID 25487101. Cite error: The named reference ":3" was defined multiple times with different content (see the help page).
  14. ^ Toettcher, Jared E.; Mock, Caroline; Batchelor, Eric; Loewer, Alexander; Lahav, Galit (2010-09-28). "A synthetic–natural hybrid oscillator in human cells". Proceedings of the National Academy of Sciences of the United States of America. 107 (39): 17047–17052. doi:10.1073/pnas.1005615107. ISSN 0027-8424. PMC 2947868. PMID 20837528.
  15. ^ a b Elowitz, Michael B.; Leibler, Stanislas (2000-01). "A synthetic oscillatory network of transcriptional regulators". Nature. 403 (6767): 335–338. doi:10.1038/35002125. ISSN 1476-4687. {{cite journal}}: Check date values in: |date= (help)
  16. ^ Bashor, Caleb J.; Collins, James J. (05 20, 2018). "Understanding Biological Regulation Through Synthetic Biology". Annual Review of Biophysics. 47: 399–423. doi:10.1146/annurev-biophys-070816-033903. ISSN 1936-1238. PMID 29547341. {{cite journal}}: Check date values in: |date= (help)
  17. ^ Jones, Daniel L.; Brewster, Robert C.; Phillips, Rob (2014-12-19). "Promoter architecture dictates cell-to-cell variability in gene expression". Science (New York, N.Y.). 346 (6216): 1533–1536. doi:10.1126/science.1255301. ISSN 1095-9203. PMC 4388425. PMID 25525251.
  18. ^ Myers, Chris (2018). Engineering Genetic Circuits. New York: CRC Press. p. 39. ISBN 9780429193057.
  19. ^ a b c Kassaw, Tessema K.; Donayre-Torres, Alberto J.; Antunes, Mauricio S.; Morey, Kevin J.; Medford, June I. (2018-08-01). "Engineering synthetic regulatory circuits in plants". Plant Science. Synthetic Biology Meets Plant Metabolism. 273: 13–22. doi:10.1016/j.plantsci.2018.04.005. ISSN 0168-9452.
  20. ^ Yokobayashi, Y.; Weiss, R.; Arnold, F. H. (2002-11-25). "Directed evolution of a genetic circuit". Proceedings of the National Academy of Sciences. 99 (26): 16587–16591. doi:10.1073/pnas.252535999. ISSN 0027-8424.
  21. ^ Sprinzak, David; Elowitz, Michael B. (2005-11-24). "Reconstruction of genetic circuits". Nature. 438 (7067): 443–448. doi:10.1038/nature04335. ISSN 1476-4687. PMID 16306982.
  22. ^ a b Julve Parreño, Jose Manuel; Huet, Estefanía; Fernández-Del-Carmen, Asun; Segura, Alvaro; Venturi, Micol; Gandía, Antoni; Pan, Wei-Song; Albaladejo, Irene; Forment, Javier; Pla, Davinia; Wigdorovitz, Andrés (03 2018). "A synthetic biology approach for consistent production of plant-made recombinant polyclonal antibodies against snake venom toxins". Plant Biotechnology Journal. 16 (3): 727–736. doi:10.1111/pbi.12823. ISSN 1467-7652. PMC 5814581. PMID 28850773. {{cite journal}}: Check date values in: |date= (help)
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