Home LiteratureArticle Details
PMID: 15534694 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Conservation and evolution of cis-regulatory systems in ascomycete fungi.

PLoS biology ·Vol. 2 ·No. 12 ·2004-12-00 ·Pages e398

Gasch AP, Moses AM, Chiang DY, Fraser HB, Berardini M, Eisen MB

Abstract

Relatively little is known about the mechanisms through which gene expression regulation evolves. To investigate this, we systematically explored the conservation of regulatory networks in fungi by examining the cis-regulatory elements that govern the expression of coregulated genes. We first identified groups of coregulated Saccharomyces cerevisiae genes enriched for genes with known upstream or downstream cis-regulatory sequences. Reasoning that many of these gene groups are coregulated in related species as well, we performed similar analyses on orthologs of coregulated S. cerevisiae genes in 13 other ascomycete species. We find that many species-specific gene groups are enriched for the same flanking regulatory sequences as those found in the orthologous gene groups fromS. cerevisiae, indicating that those regulatory systems have been conserved in multiple ascomycete species. In addition to these clear cases of regulatory conservation, we find examples of cis-element evolution that suggest multiple modes of regulatory diversification, including alterations in transcription factor-binding specificity, incorporation of new gene targets into an existing regulatory system, and cooption of regulatory systems to control a different set of genes. We investigated one example in greater detail by measuring the in vitro activity of the S. cerevisiae transcription factor Rpn4p and its orthologs from Candida albicans and Neurospora crassa. Our results suggest that the DNA binding specificity of these proteins has coevolved with the sequences found upstream of the Rpn4p target genes and suggest that Rpn4p has a different function in N. crassa.

MeSH Terms
Amino Acid Motifs Amino Acid Sequence Ascomycota/genetics Binding, Competitive Candida albicans/genetics Cloning, Molecular Conserved Sequence DNA/chemistry,metabolism DNA-Binding Proteins/metabolism Evolution, Molecular Gene Expression Regulation, Fungal Genes, Regulator Genome, Fungal Models, Statistical Molecular Sequence Data Multigene Family Neurospora crassa/genetics Open Reading Frames Phylogeny Plasmids/metabolism Proteasome Endopeptidase Complex/metabolism Protein Binding Saccharomyces cerevisiae/genetics Saccharomyces cerevisiae Proteins/metabolism Sequence Homology, Amino Acid Species Specificity Transcription Factors/metabolism
Chemicals
DNA-Binding Proteins RPN4 protein, S cerevisiae Saccharomyces cerevisiae Proteins Transcription Factors DNA Proteasome Endopeptidase Complex
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Gasch Audrey P
Genome Sciences Department, Genomics Division, Lawrence Berkeley National Laboratory , Berkeley, California, USA. agasch@wisc.edu <agasch@wisc.edu>
Moses Alan M
Chiang Derek Y
Fraser Hunter B
Berardini Mark
Eisen Michael B
Conflict of Interest

The authors have declared that no conflicts of interest exist.

References (120)
120 references, click to expand
  1. SWI6 is a regulatory subunit of two different cell cycle START-dependent transcription factors in Saccharomyces cerevisiae.
    J Cell Sci Suppl. 1992;16:87-96 PMID: 1297653
  2. Mapping of neutralizing epitopes and the receptor binding site of human interleukin 1 beta.
    J Biol Chem. 1993 May 5;268(13):9771-9 PMID: 7683661
  3. E2F site activates transcription in fission yeast Schizosaccharomyces pombe and binds to a 30-kDa transcription factor.
    J Biol Chem. 1993 Sep 25;268(27):20392-401 PMID: 8376397
  4. MCB elements and the regulation of DNA replication genes in yeast.
    Curr Genet. 1993 Sep;24(3):185-92 PMID: 8221925
  5. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice.
    Nucleic Acids Res. 1994 Nov 11;22(22):4673-80 PMID: 7984417
  6. DNA binding site specificity of the Neurospora global nitrogen regulatory protein NIT2: analysis with mutated binding sites.
    Mol Gen Genet. 1994 Nov 15;245(4):512-6 PMID: 7808401
  7. Evolutionary dynamics of the enhancer region of even-skipped in Drosophila.
    Mol Biol Evol. 1995 Nov;12(6):1002-11 PMID: 8524036
  8. Fitting a mixture model by expectation maximization to discover motifs in biopolymers.
    Proc Int Conf Intell Syst Mol Biol. 1994;2:28-36 PMID: 7584402
  9. DNA recognition by Cys2His2 zinc finger proteins.
    Annu Rev Biophys Biomol Struct. 2000;29:183-212 PMID: 10940247
  10. The core meiotic transcriptome in budding yeasts.
    Nat Genet. 2000 Dec;26(4):415-23 PMID: 11101837
  11. Genomic expression programs in the response of yeast cells to environmental changes.
    Mol Biol Cell. 2000 Dec;11(12):4241-57 PMID: 11102521
  12. New components of a system for phosphate accumulation and polyphosphate metabolism in Saccharomyces cerevisiae revealed by genomic expression analysis.
    Mol Biol Cell. 2000 Dec;11(12):4309-21 PMID: 11102525
  13. Signal transduction cascades regulating fungal development and virulence.
    Microbiol Mol Biol Rev. 2000 Dec;64(4):746-85 PMID: 11104818
  14. YPD, PombePD and WormPD: model organism volumes of the BioKnowledge library, an integrated resource for protein information.
    Nucleic Acids Res. 2001 Jan 1;29(1):75-9 PMID: 11125054
  15. Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF.
    Nature. 2001 Jan 25;409(6819):533-8 PMID: 11206552
  16. Regulatory element detection using correlation with expression.
    Nat Genet. 2001 Feb;27(2):167-71 PMID: 11175784
  17. RPN4 is a ligand, substrate, and transcriptional regulator of the 26S proteasome: a negative feedback circuit.
    Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3056-61 PMID: 11248031
  18. The second STE12 homologue of Cryptococcus neoformans is MATa-specific and plays an important role in virulence.
    Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3258-63 PMID: 11248066
  19. Combining phylogenetic data with co-regulated genes to identify regulatory motifs.
    Bioinformatics. 2003 Dec 12;19(18):2369-80 PMID: 14668220
  20. Whole-genome discovery of transcription factor binding sites by network-level conservation.
    Genome Res. 2004 Jan;14(1):99-108 PMID: 14672978
  21. Transcriptional remodeling in response to iron deprivation in Saccharomyces cerevisiae.
    Mol Biol Cell. 2004 Mar;15(3):1233-43 PMID: 14668481
  22. Extensive association of functionally and cytotopically related mRNAs with Puf family RNA-binding proteins in yeast.
    PLoS Biol. 2004 Mar;2(3):E79 PMID: 15024427
  23. Proof and evolutionary analysis of ancient genome duplication in the yeast Saccharomyces cerevisiae.
    Nature. 2004 Apr 8;428(6983):617-24 PMID: 15004568
  24. The Ashbya gossypii genome as a tool for mapping the ancient Saccharomyces cerevisiae genome.
    Science. 2004 Apr 9;304(5668):304-7 PMID: 15001715
  25. The diploid genome sequence of Candida albicans.
    Proc Natl Acad Sci U S A. 2004 May 11;101(19):7329-34 PMID: 15123810
  26. Annotation transfer between genomes: protein-protein interologs and protein-DNA regulogs.
    Genome Res. 2004 Jun;14(6):1107-18 PMID: 15173116
  27. WebLogo: a sequence logo generator.
    Genome Res. 2004 Jun;14(6):1188-90 PMID: 15173120
  28. Evolution of regulatory elements producing a conserved gene expression pattern in Caenorhabditis.
    Evol Dev. 2004 Jul-Aug;6(4):237-45 PMID: 15230964
  29. Periodic gene expression program of the fission yeast cell cycle.
    Nat Genet. 2004 Aug;36(8):809-17 PMID: 15195092
  30. Two types of molecular evolution. Evidence from studies of interspecific hybridization.
    Proc Natl Acad Sci U S A. 1974 Jul;71(7):2843-7 PMID: 4212492
  31. Biochemical evolution.
    Annu Rev Biochem. 1977;46:573-639 PMID: 409339
  32. The yeast STE12 product is required for expression of two sets of cell-type specific genes.
    Cell. 1985 Oct;42(3):923-30 PMID: 3931921
  33. Molecular evidence for the early colonization of land by fungi and plants.
    Science. 2001 Aug 10;293(5532):1129-33 PMID: 11498589
  34. Rapid evolution of cis-regulatory sequences via local point mutations.
    Mol Biol Evol. 2001 Sep;18(9):1764-70 PMID: 11504856
  35. Serial regulation of transcriptional regulators in the yeast cell cycle.
    Cell. 2001 Sep 21;106(6):697-708 PMID: 11572776
  36. Genomic expression responses to DNA-damaging agents and the regulatory role of the yeast ATR homolog Mec1p.
    Mol Biol Cell. 2001 Oct;12(10):2987-3003 PMID: 11598186
  37. Design and selection of novel Cys2His2 zinc finger proteins.
    Annu Rev Biochem. 2001;70:313-40 PMID: 11395410
  38. The activation domain of GAL4 protein mediates cooperative promoter binding with general transcription factors in vivo.
    Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10683-7 PMID: 7479865
  39. Towards an understanding of protein-DNA recognition.
    Philos Trans R Soc Lond B Biol Sci. 1996 Apr 29;351(1339):501-9 PMID: 8735272
  40. Life with 6000 genes.
    Science. 1996 Oct 25;274(5287):546, 563-7 PMID: 8849441
  41. Position-dependent transcriptional regulation of the murine dihydrofolate reductase promoter by the E2F transactivation domain.
    Mol Cell Biol. 1997 Apr;17(4):1966-76 PMID: 9121444
  42. Genetic regulation of nitrogen metabolism in the fungi.
    Microbiol Mol Biol Rev. 1997 Mar;61(1):17-32 PMID: 9106362
  43. The gene encoding the major proline transporter of Aspergillus nidulans is upregulated during conidiospore germination and in response to proline induction and amino acid starvation.
    Mol Microbiol. 1997 Apr;24(1):105-17 PMID: 9140969
  44. Crustacean appendage evolution associated with changes in Hox gene expression.
    Nature. 1997 Aug 14;388(6643):682-6 PMID: 9262403
  45. Long human-mouse sequence alignments reveal novel regulatory elements: a reason to sequence the mouse genome.
    Genome Res. 1997 Oct;7(10):959-66 PMID: 9331366
  46. Exploring the metabolic and genetic control of gene expression on a genomic scale.
    Science. 1997 Oct 24;278(5338):680-6 PMID: 9381177
  47. Genetic mechanisms and constraints governing the evolution of correlated traits in drosophilid flies.
    Nature. 2003 Aug 21;424(6951):931-5 PMID: 12931186
  48. The economics of ribosome biosynthesis in yeast.
    Trends Biochem Sci. 1999 Nov;24(11):437-40 PMID: 10542411
  49. Prediction of transcription regulatory sites in Archaea by a comparative genomic approach.
    Nucleic Acids Res. 2000 Feb 1;28(3):695-705 PMID: 10637320
  50. Evidence for stabilizing selection in a eukaryotic enhancer element.
    Nature. 2000 Feb 3;403(6769):564-7 PMID: 10676967
  51. Computational identification of cis-regulatory elements associated with groups of functionally related genes in Saccharomyces cerevisiae.
    J Mol Biol. 2000 Mar 10;296(5):1205-14 PMID: 10698627
  52. Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons.
    Science. 2000 Apr 7;288(5463):136-40 PMID: 10753117
  53. A STE12 homolog is required for mating but dispensable for filamentation in candida lusitaniae.
    Genetics. 2000 May;155(1):17-29 PMID: 10790381
  54. Aspergillus SteA (sterile12-like) is a homeodomain-C2/H2-Zn+2 finger transcription factor required for sexual reproduction.
    Mol Microbiol. 2000 Apr;36(2):290-301 PMID: 10792717
  55. Conservation of DNA regulatory motifs and discovery of new motifs in microbial genomes.
    Genome Res. 2000 Jun;10(6):744-57 PMID: 10854408
  56. Genome-wide characterization of the Zap1p zinc-responsive regulon in yeast.
    Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):7957-62 PMID: 10884426
  57. 20S proteasome biogenesis.
    Biochimie. 2001 Mar-Apr;83(3-4):289-93 PMID: 11295488
  58. Developmental system drift and flexibility in evolutionary trajectories.
    Evol Dev. 2001 Mar-Apr;3(2):109-19 PMID: 11341673
  59. Transcriptional profiling shows that Gcn4p is a master regulator of gene expression during amino acid starvation in yeast.
    Mol Cell Biol. 2001 Jul;21(13):4347-68 PMID: 11390663
  60. Protein dispensability and rate of evolution.
    Nature. 2001 Jun 28;411(6841):1046-9 PMID: 11429604
  61. Identifying target sites for cooperatively binding factors.
    Bioinformatics. 2001 Jul;17(7):608-21 PMID: 11448879
  62. Promoter-specific binding of Rap1 revealed by genome-wide maps of protein-DNA association.
    Nat Genet. 2001 Aug;28(4):327-34 PMID: 11455386
  63. Analysis of conserved noncoding DNA in Drosophila reveals similar constraints in intergenic and intronic sequences.
    Genome Res. 2001 Aug;11(8):1335-45 PMID: 11483574
  64. Transcriptional regulatory networks in Saccharomyces cerevisiae.
    Science. 2002 Oct 25;298(5594):799-804 PMID: 12399584
  65. Abundant raw material for cis-regulatory evolution in humans.
    Mol Biol Evol. 2002 Nov;19(11):1991-2004 PMID: 12411608
  66. Probabilistic code for DNA recognition by proteins of the EGR family.
    J Mol Biol. 2002 Nov 1;323(4):701-27 PMID: 12419259
  67. Exploring the conditional coregulation of yeast gene expression through fuzzy k-means clustering.
    Genome Biol. 2002 Oct 10;3(11):RESEARCH0059 PMID: 12429058
  68. Discovery of novel transcription factor binding sites by statistical overrepresentation.
    Nucleic Acids Res. 2002 Dec 15;30(24):5549-60 PMID: 12490723
  69. Autoregulation in the biosynthesis of ribosomes.
    Mol Cell Biol. 2003 Jan;23(2):699-707 PMID: 12509467
  70. Saccharomyces Genome Database (SGD) provides biochemical and structural information for budding yeast proteins.
    Nucleic Acids Res. 2003 Jan 1;31(1):216-8 PMID: 12519985
  71. Global transcriptional responses of fission yeast to environmental stress.
    Mol Biol Cell. 2003 Jan;14(1):214-29 PMID: 12529438
  72. Identification of co-regulated genes through Bayesian clustering of predicted regulatory binding sites.
    Nat Biotechnol. 2003 Apr;21(4):435-9 PMID: 12627170
  73. Stress-induced gene expression in Candida albicans: absence of a general stress response.
    Mol Biol Cell. 2003 Apr;14(4):1460-7 PMID: 12686601
  74. Tracing the evolutionary history of Drosophila regulatory regions with models that identify transcription factor binding sites.
    Mol Biol Evol. 2003 May;20(5):703-14 PMID: 12679540
  75. The genome sequence of the filamentous fungus Neurospora crassa.
    Nature. 2003 Apr 24;422(6934):859-68 PMID: 12712197
  76. Phylogenetic relationships among yeasts of the 'Saccharomyces complex' determined from multigene sequence analyses.
    FEMS Yeast Res. 2003 Jun;3(4):417-32 PMID: 12748053
  77. Sequencing and comparison of yeast species to identify genes and regulatory elements.
    Nature. 2003 May 15;423(6937):241-54 PMID: 12748633
  78. Multiple sequence alignment with the Clustal series of programs.
    Nucleic Acids Res. 2003 Jul 1;31(13):3497-500 PMID: 12824352
  79. Finding functional features in Saccharomyces genomes by phylogenetic footprinting.
    Science. 2003 Jul 4;301(5629):71-6 PMID: 12775844
  80. Phylogenetically and spatially conserved word pairs associated with gene-expression changes in yeasts.
    Genome Biol. 2003;4(7):R43 PMID: 12844359
  81. Conservation of Endo16 expression in sea urchins despite evolutionary divergence in both cis and trans-acting components of transcriptional regulation.
    Development. 2003 Sep;130(17):4187-99 PMID: 12874137
  82. The evolution of transcriptional regulation in eukaryotes.
    Mol Biol Evol. 2003 Sep;20(9):1377-419 PMID: 12777501
  83. Nitrogen metabolism and virulence of Candida albicans require the GATA-type transcriptional activator encoded by GAT1.
    Mol Microbiol. 2003 Nov;50(3):993-1004 PMID: 14617156
  84. E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints.
    Genes Dev. 2002 Jan 15;16(2):245-56 PMID: 11799067
  85. The evolution of DNA regulatory regions for proteo-gamma bacteria by interspecies comparisons.
    Genome Res. 2002 Feb;12(2):298-308 PMID: 11827949
  86. The genome sequence of Schizosaccharomyces pombe.
    Nature. 2002 Feb 21;415(6874):871-80 PMID: 11859360
  87. The genetics of the E2F family of transcription factors: shared functions and unique roles.
    Biochim Biophys Acta. 2002 Jun 21;1602(2):131-50 PMID: 12020800
  88. Nitrogen regulation in Saccharomyces cerevisiae.
    Gene. 2002 May 15;290(1-2):1-18 PMID: 12062797
  89. Evolution of transcription factor binding sites in Mammalian gene regulatory regions: conservation and turnover.
    Mol Biol Evol. 2002 Jul;19(7):1114-21 PMID: 12082130
  90. Genome-wide analysis of gene expression regulated by the calcineurin/Crz1p signaling pathway in Saccharomyces cerevisiae.
    J Biol Chem. 2002 Aug 23;277(34):31079-88 PMID: 12058033
  91. Evolutionary divergence of vertebrate Hoxb2 expression patterns and transcriptional regulatory loci.
    J Exp Zool. 2002 Oct 15;294(3):285-99 PMID: 12362434
  92. Gene co-option in physiological and morphological evolution.
    Annu Rev Cell Dev Biol. 2002;18:53-80 PMID: 12142278
  93. Gcn4 co-ordinates morphogenetic and metabolic responses to amino acid starvation in Candida albicans.
    EMBO J. 2002 Oct 15;21(20):5448-56 PMID: 12374745
  94. Functional analysis of eve stripe 2 enhancer evolution in Drosophila: rules governing conservation and change.
    Development. 1998 Mar;125(5):949-58 PMID: 9449677
  95. Extracting regulatory sites from the upstream region of yeast genes by computational analysis of oligonucleotide frequencies.
    J Mol Biol. 1998 Sep 4;281(5):827-42 PMID: 9719638
  96. Multiple transcriptional activation complexes tether the yeast activator Met4 to DNA.
    EMBO J. 1998 Nov 2;17(21):6327-36 PMID: 9799240
  97. Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization.
    Mol Biol Cell. 1998 Dec;9(12):3273-97 PMID: 9843569
  98. Cluster analysis and display of genome-wide expression patterns.
    Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14863-8 PMID: 9843981
  99. Analysis of zinc fingers optimized via phage display: evaluating the utility of a recognition code.
    J Mol Biol. 1999 Feb 5;285(5):1917-34 PMID: 9925775
  100. BIACORE: an affinity biosensor system for characterization of biomolecular interactions.
    Biochem Soc Trans. 1999 Feb;27(2):335-40 PMID: 10093759
  101. Rpn4p acts as a transcription factor by binding to PACE, a nonamer box found upstream of 26S proteasomal and other genes in yeast.
    FEBS Lett. 1999 Apr 30;450(1-2):27-34 PMID: 10350051
  102. Evidence for redundancy but not trans factor-cis element coevolution in the regulation of Drosophila Yp genes.
    Genetics. 1999 Jun;152(2):605-16 PMID: 10353903
  103. Systematic determination of genetic network architecture.
    Nat Genet. 1999 Jul;22(3):281-5 PMID: 10391217
  104. Subcellular localization, stoichiometry, and protein levels of 26 S proteasome subunits in yeast.
    J Biol Chem. 1999 Jul 30;274(31):21943-52 PMID: 10419517
  105. Evolutionary alterations of the minimal promoter for notochord-specific Brachyury expression in ascidian embryos.
    Development. 1999 Sep;126(17):3725-34 PMID: 10433903
  106. Context-dependent transcriptional regulation.
    J Biol Chem. 1999 Oct 15;274(42):29583-6 PMID: 10514422
  107. Teleonomic mechanisms in cellular metabolism, growth, and differentiation.
    Cold Spring Harb Symp Quant Biol. 1961;26:389-401 PMID: 14475415
  108. Detecting putative orthologs.
    Bioinformatics. 2003 Sep 1;19(13):1710-1 PMID: 15593400
  109. PAML: a program package for phylogenetic analysis by maximum likelihood.
    Comput Appl Biosci. 1997 Oct;13(5):555-6 PMID: 9367129
  110. Cephalopod Hox genes and the origin of morphological novelties.
    Nature. 2003 Aug 28;424(6952):1061-5 PMID: 12944969
  111. Functional tests of enhancer conservation between distantly related species.
    Development. 2003 Nov;130(21):5133-42 PMID: 12944426
  112. Gene loss, protein sequence divergence, gene dispensability, expression level, and interactivity are correlated in eukaryotic evolution.
    Genome Res. 2003 Oct;13(10):2229-35 PMID: 14525925
  113. Position specific variation in the rate of evolution in transcription factor binding sites.
    BMC Evol Biol. 2003 Aug 28;3:19 PMID: 12946282
  114. Plant cell cycle transitions.
    Curr Opin Plant Biol. 2003 Dec;6(6):536-43 PMID: 14611951
  115. Developmental gene regulatory network architecture across 500 million years of echinoderm evolution.
    Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13356-61 PMID: 14595011
  116. The general control of amino acid biosynthetic genes in the yeast Saccharomyces cerevisiae.
    CRC Crit Rev Biochem. 1986;21(3):277-317 PMID: 3536302
  117. The regulatory gene areA mediating nitrogen metabolite repression in Aspergillus nidulans. Mutations affecting specificity of gene activation alter a loop residue of a putative zinc finger.
    EMBO J. 1990 May;9(5):1355-64 PMID: 1970293
  118. cpc-1, the general regulatory gene for genes of amino acid biosynthesis in Neurospora crassa, is differentially expressed during the asexual life cycle.
    Mol Cell Biol. 1991 Feb;11(2):928-34 PMID: 1824959
  119. Control of DNA synthesis genes in fission yeast by the cell-cycle gene cdc10+.
    Nature. 1992 Jan 30;355(6359):449-53 PMID: 1734281
  120. Nucleosome core displacement in vitro via a metastable transcription factor-nucleosome complex.
    Science. 1992 Dec 11;258(5089):1780-4 PMID: 1465613
Article Info
Journal
PLoS biology
Abbr.
PLoS Biol
ISSN
1545-7885
DOI
10.1371/journal.pbio.0020398
Email
agasch@wisc.edu
Published
2004-12-00
Epub
2004-00-09
Pages
e398
Language
English
Region
United States
NLM ID
101183755
PMCID
PMC526180
Subset
IM
Grants
NCI NIH HHS · P01 CA092584 · United States
NCI NIH HHS · 5P01CA092584-03 · United States
External Links
PubMed source DOI: 10.1371/journal.pbio.0020398 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2