title: Synthetic circuit for exact adaptation and fold-change detection.
abstract: Biological organisms use their sensory systems to detect changes in their environment. The ability of sensory systems to adapt to static inputs allows wide dynamic range as well as sensitivity to input changes including fold-change detection, a response that depends only on fold changes in input, and not on absolute changes. This input scale invariance underlies an important strategy for search that depends solely on the spatial profile of the input. Synthetic efforts to reproduce the architecture and response of cellular circuits provide an important step to foster understanding at the molecular level. We report the bottom-up assembly of biochemical systems that show exact adaptation and fold-change detection. Using a malachite green aptamer as the output, a synthetic transcriptional circuit with the connectivity of an incoherent feed-forward loop motif exhibits pulse generation and exact adaptation. A simple mathematical model was used to assess the amplitude and duration of pulse response as well as the parameter regimes required for fold-change detection. Upon parameter tuning, this synthetic circuit exhibits fold-change detection for four successive rounds of two-fold input changes. The experimental realization of fold-change detection circuit highlights the programmability of transcriptional switches and the ability to obtain predictive dynamical systems in a cell-free environment for technological applications.
authors.affiliation: Department of Bioengineering, California Institute of Technology, Pasadena, CA 91125, USA jongmin@dna.caltech.edu.
authors.forename: Jongmin
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Computer Science, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Ishan
authors.initials: I
authors.lastname: Khetarpal
authors.affiliation: Department of Control and Dynamical Systems, California Institute of Technology, Pasadena, CA 91125, USA jongmin@dna.caltech.edu.
authors.forename: Shaunak
authors.initials: S
authors.lastname: Sen
authors.affiliation: Department of Bioengineering, California Institute of Technology, Pasadena, CA 91125, USA Department of Control and Dynamical Systems, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Murray
mesh_terms: D000465:Algorithms; D052157:Aptamers, Nucleotide / Q000737:chemistry / Q000235:genetics; D015374:Biosensing Techniques; D003198:Computer Simulation; D012321:DNA-Directed RNA Polymerases / Q000737:chemistry; D005095:Exoribonucleases / Q000737:chemistry; D005456:Fluorescent Dyes / Q000737:chemistry; D005786:Gene Expression Regulation; D008954:Models, Biological; D012394:Rosaniline Dyes / Q000737:chemistry; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000737:chemistry
chemical_list: D052157:Aptamers, Nucleotide; D005456:Fluorescent Dyes; D012394:Rosaniline Dyes; D014764:Viral Proteins; C005095:malachite green; C062210:bacteriophage T7 RNA polymerase; D012321:DNA-Directed RNA Polymerases; D005095:Exoribonucleases; C080868:ribonuclease R
references.citation: Mol Syst Biol. 2011 Feb 1;7:465
references.pmid: 21283141
references.citation: Biochemistry. 1997 Apr 8;36(14):4223-32
references.pmid: 9100017
references.citation: Nat Rev Genet. 2007 Jun;8(6):450-61
references.pmid: 17510665
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 31;109(5):1802-7
references.pmid: 22307649
references.citation: Proc Natl Acad Sci U S A. 1999 May 25;96(11):6131-6
references.pmid: 10339553
references.citation: PLoS Comput Biol. 2012;8(11):e1002748
references.pmid: 23133355
references.citation: Nat Nanotechnol. 2007 May;2(5):275-84
references.pmid: 18654284
references.citation: J Mol Biol. 2001 Jul 13;310(3):509-22
references.pmid: 11439019
references.citation: J Biol Chem. 2006 Oct 6;281(40):29769-75
references.pmid: 16893880
references.citation: Mol Syst Biol. 2006;2:68
references.pmid: 17170763
references.citation: Curr Opin Cell Biol. 2003 Apr;15(2):221-31
references.pmid: 12648679
references.citation: J R Soc Interface. 2013 Jan 04;10(80):20120935
references.pmid: 23293140
references.citation: Mol Cell. 2009 Dec 11;36(5):894-9
references.pmid: 20005851
references.citation: Sci Signal. 2012 Jan 03;5(205):ra2
references.pmid: 22215733
references.citation: ACS Nano. 2013 Jan 22;7(1):27-34
references.pmid: 23176248
references.citation: ACS Synth Biol. 2012 Aug 17;1(8):299-316
references.pmid: 23651285
references.citation: Nat Nanotechnol. 2012 Dec;7(12):816-20
references.pmid: 23202472
references.citation: J Comput Chem. 2011 Jan 15;32(1):170-3
references.pmid: 20645303
references.citation: Nature. 2011 Jul 20;475(7356):368-72
references.pmid: 21776082
references.citation: Nature. 2012 Nov 8;491(7423):249-53
references.pmid: 23041931
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6355-60
references.pmid: 15096621
references.citation: Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17669-74
references.pmid: 15591347
references.citation: Nat Genet. 2002 May;31(1):64-8
references.pmid: 11967538
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):E784-93
references.pmid: 21921236
references.citation: Nature. 1999 Jan 14;397(6715):168-71
references.pmid: 9923680
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15995-6000
references.pmid: 20729472
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13870-5
references.pmid: 21808031
references.citation: Nat Chem. 2011 Feb;3(2):103-13
references.pmid: 21258382
references.citation: Mol Syst Biol. 2011 Aug 02;7:519
references.pmid: 21811230
references.citation: Mol Cell. 2009 Dec 11;36(5):885-93
references.pmid: 20005850
references.citation: Nature. 2006 Mar 16;440(7082):297-302
references.pmid: 16541064
references.citation: Nature. 1990 Aug 30;346(6287):818-22
references.pmid: 1697402
references.citation: Mol Cell. 2013 Jan 24;49(2):213-21
references.pmid: 23352242
references.citation: Science. 2006 Dec 8;314(5805):1585-8
references.pmid: 17158324
references.citation: Science. 2012 Feb 17;335(6070):831-4
references.pmid: 22344439
references.citation: Mol Cell. 2010 Feb 12;37(3):418-28
references.pmid: 20159560
references.citation: J Am Chem Soc. 2009 Dec 2;131(47):17303-14
references.pmid: 19894722
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14855-60
references.pmid: 18812513
references.citation: Nature. 2013 May 30;497(7451):619-23
references.pmid: 23676681
references.citation: Nat Rev Microbiol. 2013 Jan;11(1):45-57
references.pmid: 23241849
references.citation: Mol Syst Biol. 2011 Feb 1;7:466
references.pmid: 21283142
references.citation: J R Soc Interface. 2013 Jan 30;10(81):20121001
references.pmid: 23365194
references.citation: Curr Opin Biotechnol. 2013 Aug;24(4):575-80
references.pmid: 23265857
references.citation: Nat Biotechnol. 2003 Sep;21(9):1069-74
references.pmid: 12923549
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17342-7
references.pmid: 23045635
references.citation: Nature. 1997 Mar 6;386(6620):69-73
references.pmid: 9052781
references.citation: Cell. 2009 Aug 21;138(4):760-73
references.pmid: 19703401
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5393-8
references.pmid: 20203007