Skip to main content
SpringerLink
Log in

Integrated analysis of transcriptome and lipid profiling reveals the co-influences of inositol–choline and Snf1 in controlling lipid biosynthesis in yeast

Molecular Genetics and Genomics volume 287, pages 541–554 (2012)Cite this article

Abstract

In the yeast Saccharomyces cerevisiae many genes involved in lipid biosynthesis are transcriptionally controlled by inositol–choline and the protein kinase Snf1. Here we undertook a global study on how inositol–choline and Snf1 interact in controlling lipid metabolism in yeast. Using both a reference strain (CEN.PK113-7D) and a snf1Δ strain cultured at different nutrient limitations (carbon and nitrogen), at a fixed specific growth rate of 0.1 h−1, and at different inositol choline concentrations, we quantified the expression of genes involved in lipid biosynthesis and the fluxes towards the different lipid components. Through integrated analysis of the transcriptome, the lipid profiling and the fluxome, it was possible to obtain a high quality, large-scale dataset that could be used to identify correlations and associations between the different components. At the transcription level, Snf1 and inositol–choline interact either directly through the main phospholipid-involving transcription factors (i.e. Ino2, Ino4, and Opi1) or through other transcription factors e.g. Gis1, Mga2, and Hac1. However, there seems to be flux regulation at the enzyme levels of several lipid involving enzymes. The analysis showed the strength of using both transcriptome and lipid profiling analysis for mapping the co-influence of inositol–choline and Snf1 on phospholipid metabolism.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Abbreviations

AcCoA:

Acetyl coenzyme A

AceAcCoA:

Acetoacetyl coenzyme A

CDP-DAG:

Cytidine diphosphate-diacylglycerol

Cho:

Choline

DAG:

Diacylglycerol

Etn:

Ethanolamine

ES:

Ergosterol

FA:

Fatty acid or fatty acyl-CoA

Glc-6-P:

Glucose 6-phosphate

G-3-P:

Glycerol 3-phosphate

HIC:

High inositol–choline

IC:

Inositol–choline

LIC:

Low inositol–choline

MaCoA:

Malonyl coenzyme A

PA:

Phosphatidic acids

PC:

Phosphatidylcholine

PE:

Phosphatidylethanolamine

PI:

Phosphatidylinositiol

PL:

Phospholipids

PS:

Phosphatidylserine

Pyr:

Pyruvate

SE:

Sterylester

ST:

Strain factor

TAG:

Triacylglycerol

TF:

Transcription factor

UASINO :

Inositol-sensitive upstream activating sequence

References

  • Abdulrehman D, Monteiro PT, Teixeira MC, Mira NP, Lourenco AB, dos Santos SC, Cabrito TR, Francisco AP, Madeira SC, Aires RS, Oliveira AL, Sa-Correia I, Freitas AT (2011) YEASTRACT: providing a programmatic access to curated transcriptional regulatory associations in Saccharomyces cerevisiae through a web services interface. Nucleic Acids Res 39(Database issue): D136–D140

    Google Scholar 

  • Alepuz PM, Cunningham KW, Estruch F (1997) Glucose repression affects ion homeostasis in yeast through the regulation of the stress-activated ENA1 gene. Mol Microbiol 26(1):91–98

    Article  PubMed  CAS  Google Scholar 

  • Ambroziak J, Henry SA (1994) INO2 and INO4 gene products, positive regulators of phospholipid biosynthesis in Saccharomyces cerevisiae, form a complex that binds to the INO1 promoter. J Biol Chem 269(21):15344–15349

    PubMed  CAS  Google Scholar 

  • Arndt KM, Ricupero-Hovasse S, Winston F (1995) TBP mutants defective in activated transcription in vivo. EMBO J 14(7):1490–1497

    PubMed  CAS  Google Scholar 

  • Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25(1):25–29

    Article  PubMed  CAS  Google Scholar 

  • Bailis AM, Poole MA, Carman GM, Henry SA (1987) The membrane-associated enzyme phosphatidylserine synthase is regulated at the level of messenger-RNA abundance. Mol Cell Biol 7(1):167–176

    PubMed  CAS  Google Scholar 

  • Balciunas D, Ronne H (1999) Yeast genes GIS1-4: multicopy suppressors of the Gal- phenotype of snf1 mig1 srb8/10/11 cells. Mol Gen Genet 262(4–5):589–599

    PubMed  CAS  Google Scholar 

  • Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate—a practical and powerful approach to multiple testing. J Roy Stat Soc B Met 57(1):289–300

    Google Scholar 

  • Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37(8):911–917

    Article  PubMed  CAS  Google Scholar 

  • Braun S, Matuschewski K, Rape M, Thoms S, Jentsch S (2002) Role of the ubiquitin-selective CDC48(UFD1/NPL4)chaperone (segregase) in ERAD of OLE1 and other substrates. EMBO J 21(4):615–621

    Article  PubMed  CAS  Google Scholar 

  • Canelas AB, Harrison N, Fazio A, Zhang J, Pitkanen JP, van den Brink J, Bakker BM, Bogner L, Bouwman J, Castrillo JI, Cankorur A, Chumnanpuen P, Daran-Lapujade P, Dikicioglu D, van Eunen K, Ewald JC, Heijnen JJ, Kirdar B, Mattila I, Mensonides FI, Niebel A, Penttila M, Pronk JT, Reuss M, Salusjarvi L, Sauer U, Sherman D, Siemann-Herzberg M, Westerhoff H, de Winde J, Petranovic D, Oliver SG, Workman CT, Zamboni N, Nielsen J (2010) Integrated multilaboratory systems biology reveals differences in protein metabolism between two reference yeast strains. Nat Commun 1:145

    Article  PubMed  Google Scholar 

  • Celenza JL, Carlson M (1984) Cloning and genetic mapping of SNF1, a gene required for expression of glucose-repressible genes in Saccharomyces cerevisiae. Mol Cell Biol 4(1):49–53

    PubMed  CAS  Google Scholar 

  • Donahue TF, Henry SA (1981) myo-Inositol-1-phosphate synthase. Characteristics of the enzyme and identification of its structural gene in yeast. J Biol Chem 256(13):7077–7085

    PubMed  CAS  Google Scholar 

  • Gancedo JM (1998) Yeast carbon catabolite repression. Microbiol Mol Biol Rev 62(2):334–361

    PubMed  CAS  Google Scholar 

  • Gaspar ML, Aregullin MA, Jesch SA, Henry SA (2006) Inositol induces a profound alteration in the pattern and rate of synthesis and turnover of membrane lipids in Saccharomyces cerevisiae. J Biol Chem 281(32):22773–22785

    Article  PubMed  CAS  Google Scholar 

  • Gavin AC, Bosche M, Krause R, Grandi P, Marzioch M, Bauer A, Schultz J, Rick JM, Michon AM, Cruciat CM, Remor M, Hofert C, Schelder M, Brajenovic M, Ruffner H, Merino A, Klein K, Hudak M, Dickson D, Rudi T, Gnau V, Bauch A, Bastuck S, Huhse B, Leutwein C, Heurtier MA, Copley RR, Edelmann A, Querfurth E, Rybin V, Drewes G, Raida M, Bouwmeester T, Bork P, Seraphin B, Kuster B, Neubauer G, Superti-Furga G (2002) Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415(6868):141–147

    Article  PubMed  CAS  Google Scholar 

  • Graves JA, Henry SA (2000) Regulation of the yeast INO1 gene. The products of the INO2, INO4 and OPI1 regulatory genes are not required for repression in response to inositol. Genetics 154(4):1485–1495

    PubMed  CAS  Google Scholar 

  • Greenberg ML, Goldwasser P, Henry SA (1982) Characterization of a yeast regulatory mutant constitutive for synthesis of inositol-1-phosphate synthase. Mol Gen Genet 186(2):157–163

    Article  PubMed  CAS  Google Scholar 

  • Henry SA, Patton-Vogt JL (1998) Genetic regulation of phospholipid metabolism: yeast as a model eukaryote. Prog Nucleic Acid Res Mol Biol 61:133–179

    Article  PubMed  CAS  Google Scholar 

  • Hiltunen JK, Mursula AM, Rottensteiner H, Wierenga RK, Kastaniotis AJ, Gurvitz A (2003) The biochemistry of peroxisomal beta-oxidation in the yeast Saccharomyces cerevisiae. FEMS Microbiol Rev 27(1):35–64

    Article  PubMed  CAS  Google Scholar 

  • Hong SP, Carlson M (2007) Regulation of snf1 protein kinase in response to environmental stress. J Biol Chem 282(23):16838–16845

    Article  PubMed  CAS  Google Scholar 

  • Jackson JC, Lopes JM (1996) The yeast UME6 gene is required for both negative and positive transcriptional regulation of phospholipid biosynthetic gene expression. Nucleic Acids Res 24(7):1322–1329

    Article  PubMed  CAS  Google Scholar 

  • Jesch SA, Zhao X, Wells MT, Henry SA (2005) Genome-wide analysis reveals inositol, not choline, as the major effector of Ino2p-Ino4p and unfolded protein response target gene expression in yeast. J Biol Chem 280(10):9106–9118

    Article  PubMed  CAS  Google Scholar 

  • Kelley MJ, Bailis AM, Henry SA, Carman GM (1988) Regulation of phospholipid biosynthesis in Saccharomyces cerevisiae by inositol. Inositol is an inhibitor of phosphatidylserine synthase activity. J Biol Chem 263(34):18078–18085

    PubMed  CAS  Google Scholar 

  • Khoomrung S, Chumnanpuen P, Jansa-ard S, Nookaew I, Nielsen J (2012). Fast and accurate preparation fatty acid methyl esters by microwave-assisted derivatization in yeast Saccharomyces cerevisiae. Accepted in Applied Microbiology and Biotechnology

  • Klig LS, Homann MJ, Carman GM, Henry SA (1985) Coordinate regulation of phospholipid biosynthesis in Saccharomyces cerevisiae—pleiotropically constitutive opil mutant. J Bacteriol 162(3):1135–1141

    PubMed  CAS  Google Scholar 

  • Kuchin S, Treich I, Carlson M (2000) A regulatory shortcut between the Snf1 protein kinase and RNA polymerase II holoenzyme. Proc Natl Acad Sci USA 97(14):7916–7920

    Article  PubMed  CAS  Google Scholar 

  • Kuchin S, Vyas VK, Carlson M (2002) Snf1 protein kinase and the repressors Nrg1 and Nrg2 regulate FLO11, haploid invasive growth, and diploid pseudohyphal differentiation. Mol Cell Biol 22(12):3994–4000

    Article  PubMed  CAS  Google Scholar 

  • Kumme J, Dietz M, Wagner C, Schuller HJ (2008) Dimerization of yeast transcription factors Ino2 and Ino4 is regulated by precursors of phospholipid biosynthesis mediated by Opi1 repressor. Curr Genet 54(1):35–45

    Article  PubMed  CAS  Google Scholar 

  • Leber R, Zinser E, Zellnig G, Paltauf F, Daum G (1994) Characterization of lipid particles of the yeast, Saccharomyces cerevisiae. Yeast 10(11):1421–1428

    Article  PubMed  CAS  Google Scholar 

  • Lin SS, Manchester JK, Gordon JI (2003) Sip2, an N-myristoylated beta subunit of Snf1 kinase, regulates aging in Saccharomyces cerevisiae by affecting cellular histone kinase activity, recombination at rDNA loci, and silencing. J Biol Chem 278(15):13390–13397

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Xu X, Kuo M-H (2010) Snf1p regulates Gcn5p transcriptional activity by antagonizing Spt3p. Genetics 184(1):91–105

    Article  PubMed  CAS  Google Scholar 

  • Lo WS, Duggan L, Emre NC, Belotserkovskya R, Lane WS, Shiekhattar R, Berger SL (2001) Snf1-a histone kinase that works in concert with the histone acetyltransferase Gcn5 to regulate transcription. Science 293(5532):1142–1146

    Article  PubMed  CAS  Google Scholar 

  • Lo WS, Gamache ER, Henry KW, Yang D, Pillus L, Berger SL (2005) Histone H3 phosphorylation can promote TBP recruitment through distinct promoter-specific mechanisms. EMBO J 24(5):997–1008

    Article  PubMed  CAS  Google Scholar 

  • Loewen CJ, Gaspar ML, Jesch SA, Delon C, Ktistakis NT, Henry SA, Levine TP (2004) Phospholipid metabolism regulated by a transcription factor sensing phosphatidic acid. Science 304(5677):1644–1647

    Article  PubMed  CAS  Google Scholar 

  • Loewen CJ, Roy A, Levine TP (2003) A conserved ER targeting motif in three families of lipid binding proteins and in Opi1p binds VAP. EMBO J 22(9):2025–2035

    Article  PubMed  CAS  Google Scholar 

  • Lopes JM, Henry SA (1991) Interaction of trans and cis regulatory elements in the INO1 promoter of Saccharomyces cerevisiae. Nucleic Acids Res 19(14):3987–3994

    Article  PubMed  CAS  Google Scholar 

  • Mullner H, Daum G (2004) Dynamics of neutral lipid storage in yeast. Acta Biochim Pol 51(2):323–347

    PubMed  Google Scholar 

  • Nath N, McCartney RR, Schmidt MC (2003) Yeast Pak1 kinase associates with and activates Snf1. Mol Cell Biol 23(11):3909–3917

    Article  PubMed  CAS  Google Scholar 

  • Nielsen J (2009) Systems biology of lipid metabolism: from yeast to human. FEBS Lett 583(24):3905–3913

    Article  PubMed  CAS  Google Scholar 

  • Nookaew I, Jewett MC, Meechai A, Thammarongtham C, Laoteng K, Cheevadhanarak S, Nielsen J, Bhumiratana S (2008) The genome-scale metabolic model iIN800 of Saccharomyces cerevisiae and its validation: a scaffold to query lipid metabolism. BMC Syst Biol 2:71

    Article  PubMed  Google Scholar 

  • Oliveira AP, Patil KR, Nielsen J (2008) Architecture of transcriptional regulatory circuits is knitted over the topology of bio-molecular interaction networks. BMC Syst Biol 2:17

    Article  PubMed  Google Scholar 

  • Patil KR, Nielsen J (2005) Uncovering transcriptional regulation of metabolism by using metabolic network topology. Proc Natl Acad Sci USA 102(8):2685–2689

    Article  PubMed  CAS  Google Scholar 

  • Portillo F, Mulet JM, Serrano R (2005) A role for the non-phosphorylated form of yeast Snf1: tolerance to toxic cations and activation of potassium transport. FEBS Lett 579(2):512–516

    Article  PubMed  CAS  Google Scholar 

  • Ratnakumar S, Young ET (2010) Snf1 dependence of peroxisomal gene expression is mediated by Adr1. J Biol Chem 285(14):10703–10714

    Article  PubMed  CAS  Google Scholar 

  • Santiago TC, Mamoun CB (2003) Genome expression analysis in yeast reveals novel transcriptional regulation by inositol and choline and new regulatory functions for Opi1p, Ino2p, and Ino4p. J Biol Chem 278(40):38723–38730

    Article  PubMed  CAS  Google Scholar 

  • Sanz P (2003) Snf1 protein kinase: a key player in the response to cellular stress in yeast. Biochem Soc Trans 31(Pt 1):178–181

    PubMed  CAS  Google Scholar 

  • Sattur AP, Karanth NG (1989a) Production of microbial lipids: II. Influence of C/N ratio-model prediction. Biotechnol Bioeng 34(6):868–871

    Article  PubMed  CAS  Google Scholar 

  • Sattur AP, Karanth NG (1989b) Production of microbial lipids: III. Influence of C/N ratio-experimental observations. Biotechnol Bioeng 34(6):872–874. doi:10.1002/bit.260340618

    Article  PubMed  CAS  Google Scholar 

  • Schaffner G, Matile P (1981) Structure and composition of bakers-yeast lipid globules. Biochemie Und Physiologie Der Pflanzen 176(7):659–666

    CAS  Google Scholar 

  • Schwank S, Ebbert R, Rautenstrauss K, Schweizer E, Schuller HJ (1995) Yeast transcriptional activator INO2 interacts as an Ino2p/Ino4p basic helix-loop-helix heteromeric complex with the inositol/choline-responsive element necessary for expression of phospholipid biosynthetic genes in Saccharomyces cerevisiae. Nucleic Acids Res 23(2):230–237

    Article  PubMed  CAS  Google Scholar 

  • Shirra MK, McCartney RR, Zhang C, Shokat KM, Schmidt MC, Arndt KM (2008) A chemical genomics study identifies Snf1 as a repressor of GCN4 translation. J Biol Chem 283(51):35889–35898

    Article  PubMed  CAS  Google Scholar 

  • Shirra MK, Patton-Vogt J, Ulrich A, Liuta-Tehlivets O, Kohlwein SD, Henry SA, Arndt KM (2001) Inhibition of acetyl coenzyme A carboxylase activity restores expression of the INO1 gene in a snf1 mutant strain of Saccharomyces cerevisiae. Mol Cell Biol 21(17):5710–5722

    Article  PubMed  CAS  Google Scholar 

  • Silversand C, Haux C (1997) Improved high-performance liquid chromatographic method for the separation and quantification of lipid classes: application to fish lipids. J Chromatogr B Biomed Sci Appl 703(1–2):7–14

    Article  PubMed  CAS  Google Scholar 

  • Soontorngun N, Larochelle M, Drouin S, Robert F, Turcotte B (2007) Regulation of gluconeogenesis in Saccharomyces cerevisiae is mediated by activator and repressor functions of Rds2. Mol Cell Biol 27(22):7895–7905

    Article  PubMed  CAS  Google Scholar 

  • Stark C, Breitkreutz BJ, Chatr-Aryamontri A, Boucher L, Oughtred R, Livstone MS, Nixon J, Van Auken K, Wang X, Shi X, Reguly T, Rust JM, Winter A, Dolinski K, Tyers M (2011) The BioGRID interaction database: 2011 update. Nucleic Acids Res 39(Database issue):D698–D704

  • Sutherland CM, Hawley SA, McCartney RR, Leech A, Stark MJ (2003) Elm1p is one of three upstream kinases for the Saccharomyces cerevisiae SNF1 complex. Curr Biol 13:1299

    Article  PubMed  CAS  Google Scholar 

  • Tehlivets O, Scheuringer K, Kohlwein SD (2007) Fatty acid synthesis and elongation in yeast. Biochim Biophys Acta 1771(3):255–270

    PubMed  CAS  Google Scholar 

  • Thomas M, Polge C (2007) SNF1/AMPK/SnRK1 kinases, global regulators at the heart of energy control? Trends Plant Sci 12(1):20–28

    Article  PubMed  Google Scholar 

  • Usaite R, Jewett MC, Oliveira AP, Yates JR 3rd, Olsson L, Nielsen J (2009) Reconstruction of the yeast Snf1 kinase regulatory network reveals its role as a global energy regulator. Mol Syst Biol 5:319

    Article  PubMed  Google Scholar 

  • van Dijken JP, Bauer J, Brambilla L, Duboc P, Francois JM, Gancedo C, Giuseppin MLF, Heijnen JJ, Hoare M, Lange HC, Madden EA, Niederberger P, Nielsen J, Parrou JL, Petit T, Porro D, Reuss M, van Riel N, Rizzi M, Steensma HY, Verrips CT, Vindelov J, Pronk JT (2000) An interlaboratory comparison of physiological and genetic properties of four Saccharomyces cerevisiae strains. Enzyme Microb Tech 26(9–10):706–714

    Article  Google Scholar 

  • Verduyn C, Postma E, Scheffers WA, Vandijken JP (1992) Effect of benzoic-acid on metabolic fluxes in yeasts—a continuous-culture study on the regulation of respiration and alcoholic fermentation. Yeast 8(7):501–517

    Article  PubMed  CAS  Google Scholar 

  • White MJ, Hirsch JP, Henry SA (1991) The OPI1 gene of Saccharomyces cerevisiae, a negative regulator of phospholipid biosynthesis, encodes a protein containing polyglutamine tracts and a leucine zipper. J Biol Chem 266(2):863–872

    PubMed  CAS  Google Scholar 

  • Woods A, Munday MR, Scott J, Yang X, Carlson M, Carling D (1994) Yeast SNF1 is functionally related to mammalian AMP-activated protein kinase and regulates acetyl-CoA carboxylase in vivo. J Biol Chem 269(30):19509–19515

    PubMed  CAS  Google Scholar 

  • Ye T, Elbing K, Hohmann S (2008) The pathway by which the yeast protein kinase Snf1p controls acquisition of sodium tolerance is different from that mediating glucose regulation. Microbiol-Sgm 154:2814–2826

    Article  CAS  Google Scholar 

  • Zaldivar J, Borges A, Johansson B, Smits HP, Villas-Boas SG, Nielsen J, Olsson L (2002) Fermentation performance and intracellular metabolite patterns in laboratory and industrial xylose-fermenting Saccharomyces cerevisiae. Appl Microbiol Biotechnol 59(4–5):436–442

    PubMed  CAS  Google Scholar 

  • Zhang J, Olsson L, Nielsen J (2010) The beta-subunits of the Snf1 kinase in Saccharomyces cerevisiae, Gal83 and Sip2, but not Sip1, are redundant in glucose derepression and regulation of sterol biosynthesis. Mol Microbiol 77(2):371–383

    Article  PubMed  CAS  Google Scholar 

  • Zhang J, Vaga S, Chumnanpuen P, Kumar R, Vemuri GN, Aebersold R, Nielsen J (2011) Mapping the interaction of Snf1 with TORC1 in Saccharomyces cerevisiae. Mol Syst Biol 7:545

    Google Scholar 

  • Zhang S, Skalsky Y, Garfinkel DJ (1999) MGA2 or SPT23 is required for transcription of the delta9 fatty acid desaturase gene, OLE1, and nuclear membrane integrity in Saccharomyces cerevisiae. Genetics 151(2):473–483

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was financed by Chalmers Foundation, the Knut and Alice Wallenberg Foundation and the Swedish Research Council (Vetenskapsrådet). We also acknowledge funding from the EU-funded project UNICELLSYS. Pramote Chumnanpuen also would like to thank the Office of the Higher Education Commission, Thailand for support by a stipend for his Ph.D. program under the program Strategic Scholarships for Frontier Research Network. We also thank Nils-Gunnar Carlsson for valuable assistance with running the HPLC-CAD, Tobias Österlund and Klaas Buijs for helpful suggestions on manuscript preparation.

Author information

Authors and Affiliations

  1. Systems and Synthetic Biology, Department of Chemical and Biological Engineering, Chalmers University of Technology, Kemivägen 10, 412 96, Gothenburg, Sweden

    Pramote Chumnanpuen, Jie Zhang, Intawat Nookaew & Jens Nielsen

Authors
  1. Pramote Chumnanpuen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Intawat Nookaew
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jens Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jens Nielsen.

Additional information

Communicated by S. Hohmann.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 1586 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chumnanpuen, P., Zhang, J., Nookaew, I. et al. Integrated analysis of transcriptome and lipid profiling reveals the co-influences of inositol–choline and Snf1 in controlling lipid biosynthesis in yeast. Mol Genet Genomics 287, 541–554 (2012). https://doi.org/10.1007/s00438-012-0697-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00438-012-0697-5

Keywords

search

Navigation