title: Emergence of switch-like behavior in a large family of simple biochemical networks.
abstract: Bistability plays a central role in the gene regulatory networks (GRNs) controlling many essential biological functions, including cellular differentiation and cell cycle control. However, establishing the network topologies that can exhibit bistability remains a challenge, in part due to the exceedingly large variety of GRNs that exist for even a small number of components. We begin to address this problem by employing chemical reaction network theory in a comprehensive in silico survey to determine the capacity for bistability of more than 40,000 simple networks that can be formed by two transcription factor-coding genes and their associated proteins (assuming only the most elementary biochemical processes). We find that there exist reaction rate constants leading to bistability in ∼90% of these GRN models, including several circuits that do not contain any of the TF cooperativity commonly associated with bistable systems, and the majority of which could only be identified as bistable through an original subnetwork-based analysis. A topological sorting of the two-gene family of networks based on the presence or absence of biochemical reactions reveals eleven minimal bistable networks (i.e., bistable networks that do not contain within them a smaller bistable subnetwork). The large number of previously unknown bistable network topologies suggests that the capacity for switch-like behavior in GRNs arises with relative ease and is not easily lost through network evolution. To highlight the relevance of the systematic application of CRNT to bistable network identification in real biological systems, we integrated publicly available protein-protein interaction, protein-DNA interaction, and gene expression data from Saccharomyces cerevisiae, and identified several GRNs predicted to behave in a bistable fashion.
authors: Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio, United States of America. dsg@mbi.osu.edu
authors: Dan
authors: D
authors: Siegal-Gaskins
authors: Maria Katherine
authors: MK
authors: Mejia-Guerra
authors: Gregory D
authors: GD
authors: Smith
authors: Erich
authors: E
authors: Grotewold
references: Biophys J. 2006 Mar 1;90(5):1546-59
references: 16339882
references: Mol Syst Biol. 2006;2:2006.0028
references: 16738572
references: Bioinformatics. 2009 Nov 1;25(21):2853-4
references: 19713415
references: Science. 2003 Jun 13;300(5626):1701-3
references: 12805536
references: Nature. 2004 Feb 19;427(6976):737-40
references: 14973486
references: Nature. 2003 Apr 10;422(6932):633-7
references: 12687005
references: Nat Rev Genet. 2009 Apr;10(4):233-40
references: 19274050
references: J Theor Biol. 2008 Jan 7;250(1):209-18
references: 17950756
references: Biophys J. 2008 Sep;95(5):2183-92
references: 18515389
references: Biophys J. 2001 Dec;81(6):3116-36
references: 11720979
references: IET Syst Biol. 2008 Mar;2(2):80-93
references: 18397119
references: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19175-80
references: 18042723
references: Cell Microbiol. 2005 Nov;7(11):1546-54
references: 16207242
references: Sci STKE. 2004 May 04;2004(232):pe20
references: 15138328
references: Proc Natl Acad Sci U S A. 2004 Jan 13;101(2):580-5
references: 14704282
references: PLoS Biol. 2010 Mar 16;8(3):e1000332
references: 20305717
references: Nat Rev Mol Cell Biol. 2001 Dec;2(12):908-16
references: 11733770
references: Annu Rev Phys Chem. 2007;58:35-55
references: 17037977
references: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7714-9
references: 12808135
references: Dev Biol. 2007 May 15;305(2):695-713
references: 17412320
references: Phys Rev Lett. 2006 May 12;96(18):188101
references: 16712399
references: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D446-51
references: 16381908
references: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):975-80
references: 12509509
references: J Theor Biol. 1995 Jan 21;172(2):169-85
references: 7891455
references: Trends Microbiol. 2005 Oct;13(10):459-62
references: 16112577
references: Mol Cell Biol. 2008 May;28(10):3139-50
references: 18299388
references: Syst Biol (Stevenage). 2005 Dec;152(4):243-8
references: 16986266
references: Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8697-702
references: 16735474
references: Mol Microbiol. 2006 Aug;61(3):564-72
references: 16879639
references: Annu Rev Microbiol. 2008;62:193-210
references: 18537474
references: Curr Opin Microbiol. 2003 Apr;6(2):163-72
references: 12732307
references: Nature. 2000 Jul 6;406(6791):90-4
references: 10894548
references: Biophys J. 2003 Mar;84(3):1606-15
references: 12609864
references: Cell. 1998 Jul 24;94(2):217-27
references: 9695950
references: J Theor Biol. 2002 May 21;216(2):229-41
references: 12079373
references: Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7834-8
references: 7644501
references: Biophys J. 2004 May;86(5):2748-57
references: 15111393
references: BMC Syst Biol. 2009 Sep 21;3:96
references: 19772572
references: Genes Dev. 2001 Sep 15;15(18):2445-56
references: 11562353
references: EMBO J. 2001 May 15;20(10):2528-35
references: 11350942
references: Biotechnol Prog. 2009 May-Jun;25(3):619-31
references: 19496142
references: Mol Microbiol. 2007 Jan;63(2):507-20
references: 17176259
references: J Biol Chem. 2004 Aug 27;279(35):36892-7
references: 15208304
references: Mol Syst Biol. 2007;3:115
references: 17551510
references: PLoS Comput Biol. 2008 Jul 18;4(7):e1000122
references: 18636099
references: Nat Biotechnol. 2001 Jun;19(6):503-4
references: 11385433
references: Nature. 2000 Jan 20;403(6767):339-42
references: 10659857
references: Genetics. 2005 May;170(1):433-46
references: 15781713
references: Mol Biol Cell. 2002 Jan;13(1):52-70
references: 11809822
references: J Theor Biol. 2000 Mar 21;203(2):117-33
references: 10704297
references: Curr Opin Biotechnol. 2008 Aug;19(4):381-8
references: 18634875
references: Biophys J. 2009 Feb;96(3):887-906
references: 19186128
references: Genetics. 1998 Aug;149(4):1633-48
references: 9691025
references: Nat Biotechnol. 2009 May;27(5):465-71
references: 19377462
references: Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2310-5
references: 15701703
references: Science. 2005 Sep 23;309(5743):2075-8
references: 16123265
references: FEBS Lett. 2009 Dec 17;583(24):3923-30
references: 19879267
references: Science. 2003 Nov 21;302(5649):1401-4
references: 14631042
references: Folia Microbiol (Praha). 2008;53(4):275-87
references: 18759110
references: J Biol Chem. 1999 Aug 6;274(32):22208-16
references: 10428786
references: Nat Cell Biol. 2003 Apr;5(4):346-51
references: 12629549
references: Cell Mol Life Sci. 2007 Mar;64(5):542-54
references: 17192808
references: Mol Microbiol. 2004 Dec;54(5):1335-51
references: 15554973
references: Mol Cell Biol. 2003 Jan;23(2):677-86
references: 12509465
references: Science. 2010 Mar 12;327(5971):1389-91
references: 20223989
references: J Mol Biol. 2008 Dec 31;384(5):1106-19
references: 18938177
references: Cold Spring Harb Symp Quant Biol. 1961;26:389-401
references: 14475415
references: PLoS Comput Biol. 2006 Sep 15;2(9):e120
references: 16978046
references: Chaos. 2001 Mar;11(1):207-220
references: 12779454
references: Nature. 2004 Sep 2;431(7004):99-104
references: 15343339
references: Cell. 2006 Aug 25;126(4):755-66
references: 16923394
references: Nucleic Acids Res. 2008 Jan;36(Database issue):D637-40
references: 18000002
references: Cell. 2000 Jun 9;101(6):573-6
references: 10892642
references: Cell. 2009 Aug 21;138(4):760-73
references: 19703401
references: Genome Biol. 2010;11(7):R74
references: 20633280