title: Major role for mRNA stability in shaping the kinetics of gene induction.
abstract: BACKGROUND
  mRNA levels in cells are determined by the relative rates of RNA production and degradation. Yet, to date, most analyses of gene expression profiles were focused on mechanisms which regulate transcription, while the role of mRNA stability in modulating transcriptional networks was to a large extent overlooked. In particular, kinetic waves in transcriptional responses are usually interpreted as resulting from sequential activation of transcription factors.
  
  
  RESULTS
  In this study, we examined on a global scale the role of mRNA stability in shaping the kinetics of gene response. Analyzing numerous expression datasets we revealed a striking global anti-correlation between rapidity of induction and mRNA stability, fitting the prediction of a kinetic mathematical model. In contrast, the relationship between kinetics and stability was less significant when gene suppression was analyzed. Frequently, mRNAs that are stable under standard conditions were very rapidly down-regulated following stimulation. Such effect cannot be explained even by a complete shut-off of transcription, and therefore indicates intense modulation of RNA stability.
  
  
  CONCLUSIONS
  Taken together, our results demonstrate the key role of mRNA stability in determining induction kinetics in mammalian transcriptional networks.
authors.affiliation: Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. r.elkon@nki.nl
authors.forename: Ran
authors.initials: R
authors.lastname: Elkon
authors.forename: Eitan
authors.initials: E
authors.lastname: Zlotorynski
authors.forename: Karen I
authors.initials: KI
authors.lastname: Zeller
authors.forename: Reuven
authors.initials: R
authors.lastname: Agami
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D007376:Interleukin-2; D012333:RNA, Messenger
references.citation: RNA. 2009 Jun;15(6):1110-20
references.pmid: 19369426
references.citation: Science. 2007 Nov 2;318(5851):794-7
references.pmid: 17975065
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9371-6
references.pmid: 12883007
references.citation: Nucleic Acids Res. 2003 Feb 15;31(4):e15
references.pmid: 12582260
references.citation: Nat Immunol. 2009 Apr;10(4):437-43
references.pmid: 19270711
references.citation: J Interferon Cytokine Res. 2007 Dec;27(12):991-5
references.pmid: 18184039
references.citation: J Interferon Cytokine Res. 2005 Jan;25(1):1-10
references.pmid: 15684617
references.citation: Nat Immunol. 2009 Mar;10(3):281-8
references.pmid: 19198593
references.citation: Nucleic Acids Res. 2009 Jul;37(Web Server issue):W23-7
references.pmid: 19420058
references.citation: Genome Res. 2008 Jul;18(7):1180-9
references.pmid: 18411406
references.citation: RNA. 2008 Sep;14(9):1959-72
references.pmid: 18658122
references.citation: Mol Cell. 2004 Jul 23;15(2):303-13
references.pmid: 15260981
references.citation: Plant Cell. 2007 Nov;19(11):3418-36
references.pmid: 18024567
references.citation: BMC Genomics. 2007 Oct 29;8:394
references.pmid: 17967192
references.citation: BMC Genomics. 2005 May 20;6:75
references.pmid: 15907206
references.citation: Trends Genet. 2007 May;23(5):250-7
references.pmid: 17379352
references.citation: Genome Res. 2003 Aug;13(8):1863-72
references.pmid: 12902380
references.citation: Genome Biol. 2006;7(3):R25
references.pmid: 16584535
references.citation: Mol Syst Biol. 2008;4:223
references.pmid: 18854817
references.citation: Nucleic Acids Res. 2009 Sep;37(17):e115
references.pmid: 19561200
references.citation: Nat Rev Genet. 2007 Jul;8(7):533-43
references.pmid: 17572691