Validation of reference genes for quantitative expression analysis by real-time RT-PCR in Saccharomyces cerevisiae

Marie-Ange Teste1,2,3,4, Manon Duquenne1,2,3,5,4, Jean François1,2,3,4, Jean-Luc Parrou1,2,3,4
1CNRS, UMR5504, Toulouse, France
2INSA,UPS,INP
3LISBP, Toulouse, France
4Université de Toulouse
5Unité des Bactéries Lactiques et pathogènes Opportunistes, INRA - Centre de Recherche de Jouy-en-Josas, Domaine de Vilvert, Jouy-en Josas, France

Tóm tắt

Abstract Background

Real-time RT-PCR is the recommended method for quantitative gene expression analysis. A compulsory step is the selection of good reference genes for normalization. A few genes often referred to as HouseKeeping Genes (HSK), such as ACT1, RDN18 or PDA1 are among the most commonly used, as their expression is assumed to remain unchanged over a wide range of conditions. Since this assumption is very unlikely, a geometric averaging of multiple, carefully selected internal control genes is now strongly recommended for normalization to avoid this problem of expression variation of single reference genes. The aim of this work was to search for a set of reference genes for reliable gene expression analysis in Saccharomyces cerevisiae.

Results

From public microarray datasets, we selected potential reference genes whose expression remained apparently invariable during long-term growth on glucose. Using the algorithm geNorm, ALG9, TAF10, TFC1 and UBC6 turned out to be genes whose expression remained stable, independent of the growth conditions and the strain backgrounds tested in this study. We then showed that the geometric averaging of any subset of three genes among the six most stable genes resulted in very similar normalized data, which contrasted with inconsistent results among various biological samples when the normalization was performed with ACT1. Normalization with multiple selected genes was therefore applied to transcriptional analysis of genes involved in glycogen metabolism. We determined an induction ratio of 100-fold for GPH1 and 20-fold for GSY2 between the exponential phase and the diauxic shift on glucose. There was no induction of these two genes at this transition phase on galactose, although in both cases, the kinetics of glycogen accumulation was similar. In contrast, SGA1 expression was independent of the carbon source and increased by 3-fold in stationary phase.

Conclusion

In this work, we provided a set of genes that are suitable reference genes for quantitative gene expression analysis by real-time RT-PCR in yeast biological samples covering a large panel of physiological states. In contrast, we invalidated and discourage the use of ACT1 as well as other commonly used reference genes (PDA1, TDH3, RDN18, etc) as internal controls for quantitative gene expression analysis in yeast.

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Tài liệu tham khảo

Bustin SA, Benes V, Nolan T, Pfaffl MW: Quantitative real-time RT-PCR--a perspective. J Mol Endocrinol. 2005, 34 (3): 597-601.

Kubista M, Andrade JM, Bengtsson M, Forootan A, Jonak J, Lind K, Sindelka R, Sjoback R, Sjogreen B, Strombom L, et al: The real-time polymerase chain reaction. Mol Aspects Med. 2006, 27 (2-3): 95-125.

VanGuilder HD, Vrana KE, Freeman WM: Twenty-five years of quantitative PCR for gene expression analysis. Biotechniques. 2008, 44 (5): 619-626.

Wong ML, Medrano JF: Real-time PCR for mRNA quantitation. Biotechniques. 2005, 39 (1): 75-85.

Nolan T, Hands RE, Bustin SA: Quantification of mRNA using real-time RT-PCR. Nat Protoc. 2006, 1 (3): 1559-1582.

Ho-Pun-Cheung A, Cellier D, Lopez-Crapez E: [Considerations for normalisation of RT-qPCR in oncology]. Ann Biol Clin (Paris). 2008, 66 (2): 121-129.

Huggett J, Dheda K, Bustin S, Zumla A: Real-time RT-PCR normalisation; strategies and considerations. Genes Immun. 2005, 6 (4): 279-284.

Liu ZL, Slininger PJ: Universal external RNA controls for microbial gene expression analysis using microarray and qRT-PCR. J Microbiol Methods. 2007, 68 (3): 486-496.

Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001, 25 (4): 402-408.

Cikos S, Bukovska A, Koppel J: Relative quantification of mRNA: comparison of methods currently used for real-time PCR data analysis. BMC Mol Biol. 2007, 8: 113-

Pfaffl MW: Quantification strategies in real-time PCR. A-Z of quantitative PCR. Edited by: Bustin S. 2003, 5: 912-La jolla, CA, USA: International University Line (IUL)

Rebrikov DV, Trofimov D: [Real-time PCR: approaches to data analysis (a review)]. Prikl Biokhim Mikrobiol. 2006, 42 (5): 520-528.

Andersen CL, Jensen JL, Orntoft TF: Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res. 2004, 64 (15): 5245-5250.

Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F: Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002, 3 (7): RESEARCH0034-

Pfaffl MW, Tichopad A, Prgomet C, Neuvians TP: Determination of stable housekeeping genes, differentially regulated target genes and sample integrity: BestKeeper--Excel-based tool using pair-wise correlations. Biotechnol Lett. 2004, 26 (6): 509-515.

Dallas PB, Gottardo NG, Firth MJ, Beesley AH, Hoffmann K, Terry PA, Freitas JR, Boag JM, Cummings AJ, Kees UR: Gene expression levels assessed by oligonucleotide microarray analysis and quantitative real-time RT-PCR -- how well do they correlate?. BMC Genomics. 2005, 6 (1): 59-

Provenzano M, Mocellin S: Complementary techniques: validation of gene expression data by quantitative real time PCR. Adv Exp Med Biol. 2007, 593: 66-73.

Stahlberg A, Elbing K, Andrade-Garda JM, Sjogreen B, Forootan A, Kubista M: Multiway real-time PCR gene expression profiling in yeast Saccharomyces cerevisiae reveals altered transcriptional response of ADH-genes to glucose stimuli. BMC Genomics. 2008, 9: 170-

Vaudano E, Costantini A, Cersosimo M, Del Prete V, Garcia-Moruno E: Application of real-time RT-PCR to study gene expression in active dry yeast (ADY) during the rehydration phase. Int J Food Microbiol. 2009, 129 (1): 30-36.

Nailis H, Coenye T, Van Nieuwerburgh F, Deforce D, Nelis HJ: Development and evaluation of different normalization strategies for gene expression studies in Candida albicans biofilms by real-time PCR. BMC Mol Biol. 2006, 7: 25-

Fang W, Bidochka MJ: Expression of genes involved in germination, conidiogenesis and pathogenesis in Metarhizium anisopliae using quantitative real-time RT-PCR. Mycol Res. 2006, 110 (Pt 10): 1165-1171.

Bohle K, Jungebloud A, Gocke Y, Dalpiaz A, Cordes C, Horn H, Hempel DC: Selection of reference genes for normalisation of specific gene quantification data of Aspergillus niger. J Biotechnol. 2007, 132 (4): 353-358.

Francois J, Parrou JL: Reserve carbohydrates metabolism in the yeast Saccharomyces cerevisiae. FEMS Microbiol Rev. 2001, 25 (1): 125-145.

Parrou JL, Enjalbert B, Plourde L, Bauche A, Gonzalez B, Francois J: Dynamic responses of reserve carbohydrate metabolism under carbon and nitrogen limitations in Saccharomyces cerevisiae. Yeast. 1999, 15 (3): 191-203.

Gancedo C, Flores CL: The importance of a functional trehalose biosynthetic pathway for the life of yeasts and fungi. FEMS Yeast Res. 2004, 4 (4-5): 351-359.

De Risi JL, Iyer VR, Brown PO: Exploring the metabolic and genetic control of gene expression on a genomic scale. Science. 1997, 278 (5338): 680-

Gasch AP, Spellman PT, Kao CM, Carmel-Harel O, Eisen MB, Storz G, Botstein D, Brown PO: Genomic expression programs in the response of yeast cells to environmental changes. Mol Biol Cell. 2000, 11 (12): 4241-4257.

Hwang PK, Tugendreich S, Fletterick RJ: Molecular analysis of GPH1, the gene encoding glycogen phosphorylase in Saccharomyces cerevisiae. Mol Cell Biol. 1989, 9 (4): 1659-1666.

Ni HT, LaPorte DC: Response of a yeast glycogen synthase gene to stress. Mol Microbiol. 1995, 16 (6): 1197-1205.

Parrou JL, Enjalbert B, Francois J: STRE- and cAMP-independent transcriptional induction of Saccharomyces cerevisiae GSY2 encoding glycogen synthase during diauxic growth on glucose. Yeast. 1999, 15 (14): 1471-1484.

Rowen DW, Meinke M, LaPorte DC: GLC3 and GHA1 of Saccharomyces cerevisiae are allelic and encode the glycogen branching enzyme. Mol Cell Biol. 1992, 12 (1): 22-29.

Teste MA, Enjalbert B, Parrou JL, Francois JM: The Saccharomyces cerevisiae YPR184w gene encodes the glycogen debranching enzyme. FEMS Microbiol Lett. 2000, 193 (1): 105-110.

Unnikrishnan I, Miller S, Meinke M, LaPorte DC: Multiple positive and negative elements involved in the regulation of expression of GSY1 in Saccharomyces cerevisiae. J Biol Chem. 2003, 278 (29): 26450-26457.

Clancy MJ, Smith LM, Magee PT: Developmental regulation of a sporulation-specific enzyme activity in Saccharomyces cerevisiae. Mol Cell Biol. 1982, 2 (2): 171-178.

Ball CA, Jin H, Sherlock G, Weng S, Matese JC, Andrada R, Binkley G, Dolinski K, Dwight SS, Harris MA, et al: Saccharomyces Genome Database provides tools to survey gene expression and functional analysis data. Nucleic Acids Res. 2001, 29 (1): 80-81.

Faccioli P, Ciceri GP, Provero P, Stanca AM, Morcia C, Terzi V: A combined strategy of "in silico" transcriptome analysis and web search engine optimization allows an agile identification of reference genes suitable for normalization in gene expression studies. Plant Mol Biol. 2007, 63 (5): 679-688.

Lee S, Jo M, Lee J, Koh SS, Kim S: Identification of novel universal housekeeping genes by statistical analysis of microarray data. J Biochem Mol Biol. 2007, 40 (2): 226-231.

Wenzel TJ, Teunissen AW, de Steensma HY: PDA1 mRNA: a standard for quantitation of mRNA in Saccharomyces cerevisiae superior to ACT1 mRNA. Nucleic Acids Res. 1995, 23 (5): 883-884.

Choder M: A general topoisomerase I-dependent transcriptional repression in the stationary phase in yeast. Genes Dev. 1991, 5 (12A): 2315-2326.

Choder M, Young RA: A portion of RNA polymerase II molecules has a component essential for stress responses and stress survival. Mol Cell Biol. 1993, 13 (11): 6984-6991.

Monje-Casas F, Michan C, Pueyo C: Absolute transcript levels of thioredoxin- and glutathione-dependent redox systems in Saccharomyces cerevisiae: response to stress and modulation with growth. Biochem J. 2004, 383 (Pt 1): 139-147.

Rosenberg S, Coit D, Tekamp-Olson P: Glyceraldehyde-3-phosphate dehydrogenase-derived expression cassettes for constitutive synthesis of heterologous proteins. Methods Enzymol. 1990, 185: 341-351.

Kingsman SM, Cousens D, Stanway CA, Chambers A, Wilson M, Kingsman AJ: High-efficiency yeast expression vectors based on the promoter of the phosphoglycerate kinase gene. Methods Enzymol. 1990, 185: 329-341.

Hinnen A, Buxton F, Chaudhuri B, Heim J, Hottiger T, Meyhack B, Pohlig G: Gene expression in recombinant yeast. Bioprocess Technol. 1995, 22: 121-193.

Mumberg D, Muller R, Funk M: Yeast vectors for the controlled expression of heterologous proteins in different genetic backgrounds. Gene. 1995, 156 (1): 119-122.

Nacken V, Achstetter T, Degryse E: Probing the limits of expression levels by varying promoter strength and plasmid copy number in Saccharomyces cerevisiae. Gene. 1996, 175 (1-2): 253-260.

Graham IR, Chambers A: Constitutive expression vectors: PGK. Methods Mol Biol. 1997, 62: 159-169.

Chambers A, Packham EA, Graham IR: Control of glycolytic gene expression in the budding yeast (Saccharomyces cerevisiae). Current Genetics. 1995, 29 (1): 1-

Wang Z, Wilson WA, Fujino MA, Roach PJ: Antagonistic controls of autophagy and glycogen accumulation by Snf1p, the yeast homolog of AMP-activated protein kinase, and the cyclin-dependent kinase Pho85p. Mol Cell Biol. 2001, 21 (17): 5742-5752.

van Dijken JP, Bauer J, Brambilla L, Duboc P, Francois JM, Gancedo C, Giuseppin ML, Heijnen JJ, Hoare M, Lange HC, et al: An interlaboratory comparison of physiological and genetic properties of four Saccharomyces cerevisiae strains. Enzyme Microb Technol. 2000, 26 (9-10): 706-714.

Guillou V, Plourde-Owobi L, Parrou JL, Goma G, Francois J: Role of reserve carbohydrates in the growth dynamics of Saccharomyces cerevisiae. FEMS Yeast Res. 2004, 4 (8): 773-787.

Parrou JL, Francois J: A simplified procedure for a rapid and reliable assay of both glycogen and trehalose in whole yeast cells. Anal Biochem. 1997, 248 (1): 186-188.

Pfaffl MW: A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001, 29 (9): e45-