title: Origins of transcriptional transition: balance between upstream and downstream regulatory gene sequences.
abstract: By measuring individual mRNA production at the single-cell level, we investigated the lac promoter's transcriptional transition during cell growth phases. In exponential phase, variation in transition rates generates two mixed phenotypes, low and high numbers of mRNAs, by modulating their burst frequency and sizes. Independent activation of the regulatory-gene sequence does not produce bimodal populations at the mRNA level, but bimodal populations are produced when the regulatory gene is activated coordinately with the upstream and downstream region promoter sequence (URS and DRS, respectively). Time-lapse microscopy of mRNAs for lac and a variant lac promoter confirm this observation. Activation of the URS/DRS elements of the promoter reveals a counterplay behavior during cell phases. The promoter transition rate coupled with cell phases determines the mRNA and transcriptional noise. We further show that bias in partitioning of RNA does not lead to phenotypic switching. Our results demonstrate that the balance between the URS and the DRS in transcriptional regulation determines population diversity.
  
  
  OBJECTIVE
  By measuring individual mRNA production at the single-cell level, we investigated the lac promoter transcriptional transition during cell growth phases. In exponential phase, variation in transition rate generates two mixed phenotypes producing low and high numbers of mRNAs by modulating the burst frequency and size. Independent activation of the regulatory gene sequence does not produce bimodal populations at the mRNA level, while it does when activated together through the coordination of upstream/downstream promoter sequences (URS/DRS). Time-lapse microscopy of mRNAs for lac and a lac variant promoter confirm this observation. Activation of the URS/DRS elements of the promoter reveals a counterplay behavior during cell phases. The promoter transition rate coupled with cell phases determines the mRNA and transcriptional noise. We further show that bias in partitioning of RNA does not lead to phenotypic switching. Our results demonstrate that the balance between URS and DRS in transcription regulation is determining the population diversity.
authors: Molecular Signaling Laboratory, Computational Systems Biology Research Group, Signal Processing Department, Tampere University of Technology, Tampere, Finland.
authors: Adrien
authors: A
authors: Sala
authors: Molecular Signaling Laboratory, Computational Systems Biology Research Group, Signal Processing Department, Tampere University of Technology, Tampere, Finland.
authors: Muhammad
authors: M
authors: Shoaib
authors: Molecular Signaling Laboratory, Computational Systems Biology Research Group, Signal Processing Department, Tampere University of Technology, Tampere, Finland.
authors: Olga
authors: O
authors: Anufrieva
authors: Molecular Signaling Laboratory, Computational Systems Biology Research Group, Signal Processing Department, Tampere University of Technology, Tampere, Finland.
authors: Gnanavel
authors: G
authors: Mutharasu
authors: Olli
authors: O
authors: Yli-Harja
authors: Molecular Signaling Laboratory, Computational Systems Biology Research Group, Signal Processing Department, Tampere University of Technology, Tampere, Finland meenakshisundaram.kandhavelu@tut.fi.
authors: Meenakshisundaram
authors: M
authors: Kandhavelu
mesh_terms: D004926:Escherichia coli / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D007763:Lac Operon; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D012333:RNA, Messenger
references: Cell. 2008 Oct 17;135(2):216-26
references: 18957198
references: Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11310-5
references: 15277674
references: Science. 1975 Jan 10;187(4171):27-35
references: 1088926
references: J Gen Microbiol. 1956 Dec;15(3):492-511
references: 13385433
references: J Mol Biol. 1961 Jun;3:318-56
references: 13718526
references: Science. 2007 May 25;316(5828):1191-4
references: 17525339
references: Science. 2002 Aug 30;297(5586):1562-6
references: 12202833
references: J Mol Biol. 2010 Feb 12;396(1):230-44
references: 19931280
references: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12795-800
references: 12237400
references: Genome Biol. 2006;7(10):R100
references: 17076895
references: Nucleic Acids Res. 1997 Mar 15;25(6):1203-10
references: 9092630
references: FEBS Lett. 2012 Nov 2;586(21):3870-5
references: 23017207
references: Proc Natl Acad Sci U S A. 1997 Feb 4;94(3):814-9
references: 9023339
references: Bioessays. 1995 Nov;17(11):987-97
references: 8526893
references: Science. 2002 Aug 16;297(5584):1183-6
references: 12183631
references: PLoS Comput Biol. 2011 Mar;7(3):e1001100
references: 21390269
references: Nucleic Acids Res. 2001 Sep 15;29(18):3873-81
references: 11557820
references: Nat Genet. 2008 Apr;40(4):471-5
references: 18362885
references: Cell. 2005 Dec 16;123(6):1025-36
references: 16360033
references: Proc Natl Acad Sci U S A. 1957 Jul 15;43(7):553-66
references: 16590055
references: Nat Genet. 2011 Jun;43(6):554-60
references: 21532574
references: Phys Biol. 2012;9(2):026004
references: 22475987
references: Bioessays. 1996 Apr;18(4):325-32
references: 8967901
references: Nat Genet. 2014 Apr;46(4):405-8
references: 24562187
references: J Bacteriol. 2007 Dec;189(23):8746-9
references: 17905994
references: Science. 2008 Oct 17;322(5900):442-6
references: 18927393
references: Mol Biosyst. 2012 Feb;8(2):565-71
references: 22048277
references: Science. 2010 Jul 30;329(5991):533-8
references: 20671182
references: J Biol Chem. 2001 Mar 16;276(11):8165-72
references: 11062240
references: Phys Biol. 2013 Apr;10(2):026002
references: 23406725
references: Science. 2013 Dec 6;342(6163):1188-93
references: 24311680
references: Nat Rev Genet. 2005 Jun;6(6):451-64
references: 15883588
references: Cell. 1984 Nov;39(1):173-80
references: 6091909