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The importance of controlling mRNA turnover during cell proliferation

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Abstract

Microbial gene expression depends not only on specific regulatory mechanisms, but also on cellular growth because important global parameters, such as abundance of mRNAs and ribosomes, could be growth rate dependent. Understanding these global effects is necessary to quantitatively judge gene regulation. In the last few years, transcriptomic works in budding yeast have shown that a large fraction of its genes is coordinately regulated with growth rate. As mRNA levels depend simultaneously on synthesis and degradation rates, those studies were unable to discriminate the respective roles of both arms of the equilibrium process. We recently analyzed 80 different genomic experiments and found a positive and parallel correlation between both RNA polymerase II transcription and mRNA degradation with growth rates. Thus, the total mRNA concentration remains roughly constant. Some gene groups, however, regulate their mRNA concentration by uncoupling mRNA stability from the transcription rate. Ribosome-related genes modulate their transcription rates to increase mRNA levels under fast growth. In contrast, mitochondria-related and stress-induced genes lower mRNA levels by reducing mRNA stability or the transcription rate, respectively. We critically review here these results and analyze them in relation to their possible extrapolation to other organisms and in relation to the new questions they open.

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References

  • Airoldi EM, Huttenhower C, Gresham D, Lu C, Caudy AA, Dunham MJ, Broach JR, Botstein D, Troyanskaya OG (2009) Predicting cellular growth from gene expression signatures. PLoS Comput Biol 5:e1000257

    Article  PubMed  PubMed Central  Google Scholar 

  • Basehoar AD, Zanton SJ, Pugh BF (2004) Identification and distinct regulation of yeast TATA box-containing genes. Cell 116:699–709

    Article  CAS  PubMed  Google Scholar 

  • Bosdriesz E, Molenaar D, Teusink B, Bruggeman FJ (2015) How fast-growing bacteria robustly tune their ribosome concentration to approximate growth-rate maximization. FEBS J 282:2029–2044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brauer MJ, Huttenhower C, Airoldi EM, Rosenstein R, Matese JC, Gresham D, Boer VM, Troyanskaya OG, Botstein D (2008) Coordination of growth rate, cell cycle, stress response, and metabolic activity in yeast. Mol Biol Cell 19:352–367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bremer H, Dennis P (1996) Modulation of chemical composition and other parameters of the cell by growth rate in Escherichia coli and Salmonella. In: Neidhardt F (ed) 2nd edn. ASM press, Washington, pp 1553–1569

    Google Scholar 

  • Canadell D, García-Martínez J, Alepuz P, Pérez-Ortín JE, Ariño J (2015) Impact of high pH stress on yeast gene expression: a comprehensive analysis of mRNA turnover during stress responses. Biochim Biophys Acta 1849:653–664

    Article  CAS  PubMed  Google Scholar 

  • Castrillo JI, Zeef LA, Hoyle DC, Zhang N, Hayes A, Gardner DC, Cornell MJ, Petty J, Hakes L, Wardleworth L, Rash B, Brown M, Dunn WB, Broadhurst D, O’Donoghue K, Hester SS, Dunkley TP, Hart SR, Swainston N, Li P, Gaskell SJ, Paton NW, Lilley KS, Kell DB, Oliver SG (2007) Growth control of the eukaryote cell: a systems biology study in yeast. J Biol 6:4

    Article  PubMed  PubMed Central  Google Scholar 

  • Csárdi G, Franks A, Choi DS, Airoldi EM, Drummond DA (2015) Accounting for experimental noise reveals that mRNA levels, amplified by post-transcriptional processes, largely determine steady-state protein levels in yeast. PLoS Genet 11:e1005206

    Article  PubMed  PubMed Central  Google Scholar 

  • Eser P, Demel C, Maier KC, Schwalb B, Pirkl N, Martin DE, Cramer P, Tresch A (2014) Periodic mRNA synthesis and degradation co-operate during cell cycle gene expression. Mol Syst Biol 10:717

    Article  PubMed  PubMed Central  Google Scholar 

  • Ferrezuelo F, Colomina N, Palmisano A, Garí E, Gallego C, Csikász-Nagy A, Aldea M (2012) The critical size is set at a single-cell level by growth rate to attain homeostasis and adaptation. Nat Commun 3:1012

    Article  PubMed  Google Scholar 

  • García-Martínez J, Aranda A, Pérez-Ortín JE (2004) Genomic run-on evaluates transcription rates for all yeast genes and identifies gene regulatory mechanisms. Mol Cell 15:303–313

    Article  PubMed  Google Scholar 

  • García-Martínez J, González-Candelas F, Pérez-Ortín JE (2007) Common gene expression strategies revealed by genome-wide analysis in yeast. Genome Biol 8:R222

    Article  PubMed  PubMed Central  Google Scholar 

  • García-Martínez J, Delgado-Ramos L, Ayala G, Pelechano V, Medina DA, Carrasco F, González R, AndrésLeón E, Steinmetz L, Warringer J, Chávez S, Pérez-Ortín JE (2016) The cellular growth rate controls overall mRNA turnover, and modulates either transcription or degradation rates of particular gene regulons. Nucleic Acids Res (in press)

  • Gasch AP, Spellman PT, Kao CM, Carmel-Harel O, Eisen MB, Storz G, Botstein D, Brown PO (2000) Genomic expression programs in the response of yeast cells to environmental changes. Mol Biol Cell 11:4241–4257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goler-Baron V, Selitrennik M, Barkai O, Haimovich G, Lotan R, Choder M (2008) Transcription in the nucleus and mRNA decay in the cytoplasm are coupled processes. Genes Dev 22:2022–2027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gómez-Herreros F, Rodríguez-Galán O, Morillo-Huesca M, Maya D, Arista-Romero M, de la Cruz J, Chávez S, Muñoz-Centeno MC (2013) Balanced production of ribosome components is required for proper G1/S transition in Saccharomyces cerevisiae. J Biol Chem 288:31689–31700

    Article  PubMed  PubMed Central  Google Scholar 

  • Gresham D, Athanasiadou R, Neymotin B et al (2015) Global tuning of gene expression with cell growth rate. Yeast 32(Supl 1):S37

    Google Scholar 

  • Hagman A, Piškur J (2015) A study on the fundamental mechanism and the evolutionary driving forces behind aerobic fermentation in yeast. PLoS ONE 10:e0116942

    Article  PubMed  PubMed Central  Google Scholar 

  • Haimovich G, Medina DA, Causse SZ, Garber M, Millán-Zambrano G, Barkai O, Chávez S, Pérez-Ortín JE, Darzacq X, Choder M (2013) Gene expression is circular: factors for mRNA degradation also foster mRNA synthesis. Cell 153:1000–1011

    Article  CAS  PubMed  Google Scholar 

  • Harel-Sharvit L, Eldad N, Haimovich G, Barkai O, Duek L, Choder M (2010) RNA polymerase II subunits link transcription and mRNA decay to translation. Cell 143:552–563

    Article  CAS  PubMed  Google Scholar 

  • Ho YH, Gasch AP (2015) Exploiting the yeast stress-activated signaling network to inform on stress biology and disease signaling. Curr Genet 61(4):503–511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huh D, Paulsson J (2011) Random partitioning of molecules at cell division. Proc Natl Acad Sci USA 108:15004–15009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huisinga KL, Pugh BF (2004) A genome-wide housekeeping role for TFIID and a highly regulated stress-related role for SAGA in Saccharomyces cerevisiae. Mol Cell 13:573–585

    Article  CAS  PubMed  Google Scholar 

  • Ihmels J, Bergmann S, Gerami-Nejad M, Yanai I, McClellan M, Berman J, Barkai N (2005a) Rewiring of the yeast transcriptional network through the evolution of motif usage. Science 309:938–940

    Article  CAS  PubMed  Google Scholar 

  • Ihmels J, Bergmann S, Berman J, Barkai N (2005b) Comparative gene expression analysis by differential clustering approach: application to the Candida albicans transcription program. PLoS Genet 1:e39

    Article  PubMed  PubMed Central  Google Scholar 

  • Jordán-Pla A, Gupta I, de Miguel-Jiménez L, Steinmetz LM, Chávez S, Pelechano V, Pérez-Ortín JE (2015) Chromatin-dependent regulation of RNA polymerases II and III activity throughout the transcription cycle. Nucleic Acids Res 43:787–802

    Article  PubMed  Google Scholar 

  • Jorgensen P, Rupes I, Sharom JR, Schneper L, Broach JR, Tyers M (2004) A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. Genes Dev 18:2491–2505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaczanowska M, Rydén-Aulin M (2007) Ribosome biogenesis and the translation process in Escherichia coli. Microbiol Mol Biol Rev 71:477–494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kafri M, Metzl-Raz E, Jona G, Barkai N (2016) The cost of protein production. Cell Rep 14:22–31

    Article  CAS  PubMed  Google Scholar 

  • Klevecz RR, Bolen J, Forrest G, Murray DB (2004) A genome-wide oscillation in transcription gates DNA replication and cell cycle. Proc Natl Acad Sci USA 101:1200–1205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klumpp S, Zhang Z, Hwa T (2009) Growth rate-dependent global effects on gene expression in bacteria. Cell 139:1366–1375

    Article  PubMed  PubMed Central  Google Scholar 

  • Kruk JA, Dutta A, Fu J, Gilmour DS, Reese JC (2011) The multifunctional Ccr4-Not complex directly promotes transcription elongation. Genes Dev 25:581–593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kubik S, Bruzzone MJ, Jacquet P, Falcone JL, Rougemont J, Shore D (2015) Nucleosome stability distinguishes two different promoter types at all protein-coding genes in yeast. Mol Cell 60:422–434

    Article  CAS  PubMed  Google Scholar 

  • Lemons JM, Feng XJ, Bennett BD, Legesse-Miller A, Johnson EL, Raitman I, Pollina EA, Rabitz HA, Rabinowitz JD, Coller HA (2010) Quiescent fibroblasts exhibit high metabolic activity. PLoS Biol 8:e1000514

    Article  PubMed  PubMed Central  Google Scholar 

  • Levy S, Barkai N (2009) Coordination of gene expression with growth rate: a feedback or a feed-forward strategy? FEBS Lett 583:3974–3978

    Article  CAS  PubMed  Google Scholar 

  • Levy S, Ihmels J, Carmi M, Weinberger A, Friedlander G, Barkai N (2007) Strategy of transcription regulation in the budding yeast. PLoS ONE 2:e250

    Article  PubMed  PubMed Central  Google Scholar 

  • Li JJ, Biggin MD (2015) Gene expression. Statistics requantitates the central dogma. Science 347:1066–1067

    CAS  PubMed  Google Scholar 

  • Lu C, Brauer MJ, Botstein D (2009) Slow growth induces heat-shock resistance in normal and respiratory-deficient yeast. Mol Biol Cell 20:891–903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miguel A, Montón F, Li T, Gómez-Herreros F, Chávez S, Alepuz P, Pérez-Ortín JE (2013) External conditions inversely change the RNA polymerase II elongation rate and density in yeast. Biochim Biophys Acta 1829:1248–1255

    Article  CAS  PubMed  Google Scholar 

  • Miller MA, Russo J, Fischer AD, Lopez Leban FA, Olivas WM (2014) Carbon source-dependent alteration of Puf3p activity mediates rapid changes in the stabilities of mRNAs involved in mitochondrial function. Nucleic Acids Res 42:3954–3970

    Article  CAS  PubMed  Google Scholar 

  • Molin C, Jauhiainen A, Warringer J, Nerman O, Sunnerhagen P (2009) mRNA stability changes precede changes in steady-state mRNA amounts during hyperosmotic stress. RNA 15:600–614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Molina-Navarro MM, Castells-Roca L, Belli G, Garcia-Martinez J, Marin-Navarro J, Moreno J, Perez-Ortin JE, Herrero E (2008) Comprehensive transcriptional analysis of the oxidative response in yeast. J Biol Chem 283:17908–17918

    Article  CAS  PubMed  Google Scholar 

  • Newman J, Ghaemmaghami S, Ihmels J, Breslow D, Noble M, DeRisi J, Weissman J (2006) Single-cell proteomic analysis of S. cerevisiae reveals the architecture of biological noise. Nature 441:840–846

    Article  CAS  PubMed  Google Scholar 

  • O’Duibhir E, Lijnzaad P, Benschop JJ, Lenstra TL, van Leenen D, Groot Koerkamp MJ, Margaritis T, Brok MO, Kemmeren P, Holstege FC (2014) Cell cycle population effects in perturbation studies. Mol Syst Biol 10:732

    Article  PubMed  PubMed Central  Google Scholar 

  • Olivas W, Parker R (2000) The Puf3 protein is a transcript-specific regulator of mRNA degradation in yeast. EMBO J 19:6602–6611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paulsson J (2004) Summing up the noise in gene networks. Nature 427:415–418

    Article  CAS  PubMed  Google Scholar 

  • Pedersen S, Bloch PL, Reeh S, Neidhardt FC (1978) Patterns of protein synthesis in E. coli: a catalog of the amount of 140 individual proteins at different growth rates. Cell 14:179–190

    Article  CAS  PubMed  Google Scholar 

  • Pelechano V, Jimeno-González S, Rodríguez-Gil A, García-Martínez J, Pérez-Ortín JE, Chávez S (2009) Regulon-specific control of transcription elongation across the yeast genome. PLoS Genet 5:e1000614

    Article  PubMed  PubMed Central  Google Scholar 

  • Peng X, Karuturi RK, Miller LD, Lin K, Jia Y, Kondu P, Wang L, Wong LS, Liu ET, Balasubramanian MK, Liu J (2005) Identification of cell cycle-regulated genes in fission yeast. Mol Biol Cell 16:1026–1042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pérez-Ortín JE, Alepuz PM, Moreno J (2007) Genomics and gene transcription kinetics in yeast. Trends Genet 23:250–257

    Article  PubMed  Google Scholar 

  • Pérez-Ortín JE, Jordán-Pla A, Pelechano V (2011) A genomic view of mRNA turnover in yeast. C R Biol 334:647–654

    Article  PubMed  Google Scholar 

  • Pérez-Ortín JE, Alepuz P, Chávez S, Choder M (2013) Eukaryotic mRNA decay: methodologies, pathways, and links to other stages of gene expression. J Mol Biol 425:3750–3775

    Article  PubMed  Google Scholar 

  • Ramaswami M, Taylor JP, Parker R (2013) Altered ribostasis: RNA-protein granules in degenerative disorders. Cell 154:727–736

    Article  CAS  PubMed  Google Scholar 

  • Rhee HS, Pugh BF (2012) Genome-wide structure and organization of eukaryotic pre-initiation complexes. Nature 483:295–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Romero-Santacreu L, Moreno J, Perez-Ortin JE, Alepuz P (2009) Specific and global regulation of mRNA stability during osmotic stress in Saccharomyces cerevisiae. RNA 2009(15):1110–1120

    Article  Google Scholar 

  • Rustici G, Mata J, Kivinen K, Lió P, Penkett CJ, Burns G, Hayles J, Brazma A, Nurse P, Bähler J (2004) Periodic gene expression program of the fission yeast cell cycle. Nat Genet 3:809–817

    Article  Google Scholar 

  • Schell JC, Olson KA, Jiang L, Hawkins AJ, Van Vranken JG, Xie J, Egnatchik RA, Earl EG, DeBerardinis RJ, Rutter J (2014) A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol Cell 56:400–413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schuster S, Boley D, Möller P, Stark H, Kaleta C (2015) Mathematical models for explaining the Warburg effect: a review focussed on ATP and biomass production. Biochem Soc Trans 43:1187–1194

    Article  CAS  PubMed  Google Scholar 

  • Scott M, Gunderson CW, Mateescu EM, Zhang Z, Hwa T (2010) Interdependence of cell growth and gene expression: origins and consequences. Science 330:1099–1102

    Article  CAS  PubMed  Google Scholar 

  • Scott M, Klumpp S, Mateescu EM, Hwa T (2014) Emergence of robust growth laws from optimal regulation of ribosome synthesis. Mol Syst Biol 10:747

    Article  PubMed  PubMed Central  Google Scholar 

  • Shahrezaei V, Marguerat S (2015) Connecting growth with gene expression: of noise and numbers. Curr Opin Microbiol 25:127–135

    Article  CAS  PubMed  Google Scholar 

  • Shalem O, Groisman B, Choder M, Dahan O, Pilpel Y (2011) Transcriptome kinetics is governed by a genome-wide coupling of mRNA production and degradation: a role for RNA Pol II. PLoS Genet 7:e1002273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slavov N, Botstein D (2011) Coupling among growth rate response, metabolic cycle, and cell division cycle in yeast. Mol Biol Cell 22:1997–2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slavov N, Botstein D (2013) Decoupling nutrient signaling from growth rate causes aerobic glycolysis and deregulation of cell size and gene expression. Mol Biol Cell 24:157–168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slavov N, Macinskas J, Caudy A, Botstein D (2011) Metabolic cycling without cell division cycling in respiring yeast. Proc Natl Acad Sci USA 108:19090–19095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slavov N, Airoldi EM, van Oudenaarden A, Botstein D (2012) A conserved cell growth cycle can account for the environmental stress responses of divergent eukaryotes. Mol Biol Cell 23:1986–1997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solé C, Nadal-Ribelles M, de Nadal E, Posas F (2015) A novel role for lncRNAs in cell cycle control during stress adaptation. Curr Genet 61:299–308

    Article  PubMed  Google Scholar 

  • Sun M, Schwalb B, Pirkl N, Maier KC, Schenk A, Failmezger H, Tresch A, Cramer P (2013) Global analysis of eukaryotic mRNA degradation reveals Xrn1-dependent buffering of transcript levels. Mol Cell 52:52–62

    Article  CAS  PubMed  Google Scholar 

  • Tu BP, Kudlicki A, Rowicka M, McKnight SL (2005) Logic of the yeast metabolic cycle: temporal compartmentalization of cellular processes. Science 310:1152–1158

    Article  CAS  PubMed  Google Scholar 

  • van Dijk D, Dhar R, Missarova AM, Espinar L, Blevins WR, Lehner B, Carey LB (2015) Slow-growing cells within isogenic populations have increased RNA polymerase error rates and DNA damage. Nat Commun 6:7972

    Article  PubMed  PubMed Central  Google Scholar 

  • Warner JR (1999) The economics of ribosome biosynthesis in yeast. Trends Biochem Sci 24:437–440

    Article  CAS  PubMed  Google Scholar 

  • Whiteway M, Tebung WA, Choudhury BI, Rodríguez-Ortiz R (2015) Metabolic regulation in model ascomycetes–adjusting similar genomes to different lifestyles. Trends Genet 31:445–453

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We wish to thank all the members of the Valencia and Seville laboratories for their help.

Funding

This work has been supported by the Spanish MiNECO and European Union funds (FEDER) to J.E.P-O. [BFU2013-48643-C3-3-P], and to S.C. [BFU2013-48643-C3-1-P], by the Regional Valencian Government [GVPROMETEO II 2015/006] to J.E.P-O, and by the Regional Andalusian Government [P12-BIO1938MO] to S.C. L.D-R. is a recipient of an FPI fellowship from MiNECO.

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Authors and Affiliations

  1. Instituto de Biomedicina de Sevilla (IBiS), Hospital Virgen del Rocío-CSIC-Universidad de Sevilla, Seville, Spain

    Sebastián Chávez & Lidia Delgado-Ramos

  2. Departamento de Genética, Universidad de Sevilla, Seville, Spain

    Sebastián Chávez & Lidia Delgado-Ramos

  3. Departamento de Genética, Universitat de València, Burjassot, Spain

    José García-Martínez

  4. Departamento de Bioquímica y Biología Molecular, Universitat de València, Burjassot, Spain

    José E. Pérez-Ortín

  5. ERI Biotecmed, Universitat de València, Burjassot, Spain

    José García-Martínez & José E. Pérez-Ortín

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  1. Sebastián Chávez
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  2. José García-Martínez
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  3. Lidia Delgado-Ramos
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  4. José E. Pérez-Ortín
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Correspondence to Sebastián Chávez or José E. Pérez-Ortín.

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Communicated by M. Kupiec.

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Chávez, S., García-Martínez, J., Delgado-Ramos, L. et al. The importance of controlling mRNA turnover during cell proliferation. Curr Genet 62, 701–710 (2016). https://doi.org/10.1007/s00294-016-0594-2

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