Skip to main content
SpringerLink
Log in

Bioinformatic analysis of the metal response element and zinc-dependent gene regulation via the metal response element-binding transcription factor 1 in Caco-2 cells

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

The purpose of this study was to determine the correlation between the position or number of metal regulatory elements (MREs) near gene transcriptional or translational start sites, and the strength of metal response element-binding transcription factor 1 (MTF-1) regulation. A secondary analysis was performed in silico on published results measuring the effects of Zn and MTF-1 on transcriptional regulation of genes (n = 120) in the Caco-2 cell line. MRE sequence variations throughout the human genome were sorted using a position weight matrix. Three null hypotheses (H0) were tested: (1) there is no correlation between the number of MREs and MTF-1 transcriptional strength, (2) there is no correlation between the distance of the MRE upstream from the transcriptional start site (TSS) and MTF-1 transcriptional strength, and (3) there is no correlation between the distance of the MRE downstream from the translational start site (TrSS) and MTF-1 transcriptional strength. Spearman correlation was used to test for significance (p < 0.05). From our results we rejected the first H0; we observed a significant correlation between the total number of MRE sequences − 7Kbp upstream from the TSS, within the 5′ untranslated region, and + 1Kbp downstream from the TrSS, versus the strength of MTF-1 regulation (r = 0.202; p = 0.027). The second and third H0 were accepted. These results expand our understanding of the role of the MRE in Zn-dependent gene regulation. The data indicate that Zn influences the transcriptional control of gene expression beyond maintaining intracellular Zn homeostasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Agoglia RM, Fraser HB (2016) Disentangling sources of selection on exonic transcriptional enhancers. Mol Biol Evol 33:585–590

    Article  PubMed  CAS  Google Scholar 

  • Andreini C, Banci L, Bertini I, Rosato A (2006) Counting the zinc-proteins encoded in the human genome. J Proteome Res 5:196–201

    Article  PubMed  CAS  Google Scholar 

  • Andrews GK (2001) Cellular zinc sensors: MTF-1 regulation of gene expression. Biometals 14:223–237

    Article  PubMed  CAS  Google Scholar 

  • Andrews GK, Kee LD, Ravindra R, Lichtlen P, Sirito M, Sawadogo M, Schaffner W (2001) The transcription factors MTF-1 and USF1 cooperate to regulate mouse metallothionein-I expression in response to the essential metal zinc in visceral endoderm cells during early development. EMBO J 20:1114–1122

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Arora S, Rana R, Chhabra A, Jaiswal A, Rani V (2013) miRNA-transcription factor interactions: a combinatorial regulation of gene expression. Mol Genet Genomics 288:77–87

    Article  PubMed  CAS  Google Scholar 

  • Balesaria S, Ramesh B, McArdle H, Bayele HK, Srai SKS (2010) Divalent metal-dependent regulation of hepcidin expression by MTF-1. FEBS Lett 584:719–725

    Article  PubMed  CAS  Google Scholar 

  • Bellingham SA, Coleman LA, Masters CL, Camakaris J, Hill AF (2009) Regulation of prion gene expression by transcription factors SP1 and metal transcription factor-1. J Biol Chem 284:1291–1301

    Article  PubMed  CAS  Google Scholar 

  • Bembom O (2017) seqLogo: sequence logos for DNA sequence alignments. R package version 1.44.0

  • Brugnera E, Georgiev O, Radtke F, Heuchel R, Baker E, Sutherland GR, Schaffner W (1994) Cloning, chromosomal mapping and characterization of the human metal-regulatory transcription factor MTF-1. Nucleic Acids Res 22:3167–3173

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen X, Chu M, Giedroc DP (1999) MRE-binding transcription factor-1: weak zinc-binding finger domains 5 and 6 modulate the structure, affinity, and specificity of the metal-response element complex. Biochemistry 38:12915–12925

    Article  PubMed  CAS  Google Scholar 

  • Cramer M, Nagy I, Brian JM, Gassmann M, Michael OH, Georgiev O, Schaffner W (2005) NF-κB contributes to transcription of placenta growth factor and interacts with metal responsive transcription factor-1 in hypoxic human cells. Biol Chem 386:865–872

    Article  PubMed  CAS  Google Scholar 

  • Dalton TP, Solis WA, Nebert DW, Iii MJC (2000) Characterization of the MTF-1 transcription factor from zebrafish and trout cells. Comp Biochem Phys B 126:325–335

    Article  CAS  Google Scholar 

  • Grider A, Bakre AA, Laing EM, Lewis RD (2017) In silico analysis of microRNA regulation of bone development: metal response element-binding transcription factor 1 and bone signaling pathways. Austin J Nutr Metab 4:1042

    Google Scholar 

  • Günes C, Heuchel R, Georgiev O, Müller KH, Lichtlen P, Blüthmann H, Marino S, Aguzzi A, Schaffner W (1998) Embryonic lethality and liver degeneration in mice lacking the metal-responsive transcriptional activator MTF-1. EMBO J 17:2846–2854

    Article  PubMed  PubMed Central  Google Scholar 

  • Günther V, Davis AM, Georgiev O, Schaffner W (2012a) A conserved cysteine cluster, essential for transcriptional activity, mediates homodimerization of human metal-responsive transcription factor-1 (MTF-1). Biochim Biophys Acta 1823:476–483

    Article  PubMed  CAS  Google Scholar 

  • Günther V, Lindert U, Schaffner W (2012b) The taste of heavy metals: gene regulation by MTF-1. Biochim Biophys Acta 1823:1416–1425

    Article  PubMed  CAS  Google Scholar 

  • Hardyman JE, Tyson J, Jackson KA, Aldridge C, Cockell SJ, Wakeling LA, Valentine RA, Ford D (2016) Zinc sensing by metal-responsive transcription factor 1 (MTF1) controls metallothionein and ZnT1 expression to buffer the sensitivity of the transcriptome response to zinc. Metallomics 8:337–343

    Article  PubMed  CAS  Google Scholar 

  • Hogstrand C, Zheng D, Feeney G, Cunningham P, Kille P (2008) Zinc-controlled gene expression by metal-regulatory transcription factor 1 (MTF1) in a model vertebrate, the zebrafish. Biochem Soc Trans 36:1252–1257

    Article  PubMed  CAS  Google Scholar 

  • Huang L, Yan M, Kirschke CP (2010) Over-expression of ZnT7 increases insulin synthesis and secretion in pancreatic β-cells by promoting insulin gene transcription. Exp Cell Res 316:2630–2643

    Article  PubMed  CAS  Google Scholar 

  • Kearse M, Moir R, Wilson A, Stones-Havas S, Cheung M, Sturrock S, Buxton S, Cooper A, Markowitz S, Duran C, Thierer T, Ashton B, Meintjes P, Drummond A (2012) Geneious basic: an integrated and extendable desktop software platform for the organization and analysis of sequence data. Bioinformatics 28:1647–1649

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim JH, Jeon J, Shin M, Won Y, Lee M, Kwak JS, Lee G, Rhee J, Ryu JH, Chun CH, Chun JS (2014) Regulation of the catabolic cascade in osteoarthritis by the zinc-ZIP8-MTF1 axis. Cell 156:730–743

    Article  PubMed  CAS  Google Scholar 

  • Klug A (2010) The discovery of zinc fingers and their applications in gene regulation and genome manipulation. Annu Rev Biochem 79:213–231

    Article  PubMed  CAS  Google Scholar 

  • Koizumi S, Suzuki K, Ogra Y, Yamada H, Otsuka F (1999) Transcriptional activity and regulatory protein binding of metal-responsive elements of the human metallothionein-IIA gene. Eur J Biochem 259:635–642

    Article  PubMed  CAS  Google Scholar 

  • Labbé S, Prévost J, Remondelli P, Leone A, Séguin C (1991) A nuclear factor binds to the metal regulatory elements of the mouse gene encoding metallothionein-I. Nucleic Acids Res 19:4225–4231

    Article  PubMed  PubMed Central  Google Scholar 

  • Laity JH, Andrews GK (2007) Understanding the mechanisms of zinc-sensing by metal-response element binding transcription factor-1 (MTF-1). Arch Biochem Biophys 463:201–210

    Article  PubMed  CAS  Google Scholar 

  • Langmade SJ, Ravindra R, Daniels PJ, Andrews GK (2000) The transcription factor MTF-1 mediates metal regulation of the mouse ZnT1 gene. J Biol Chem 275:34803–34809

    Article  PubMed  CAS  Google Scholar 

  • Lee J, Li Z, Brower-Sinning R, John B (2007) Regulatory circuit of human microRNA biogenesis. PLoS Comput Biol 3:e67

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li B, Cui W, Tan Y, Luo P, Chen Q, Zhang C, Qu W, Miao L, Cai L (2014) Zinc is essential for the transcription function of Nrf2 in human renal tubule cells in vitro and mouse kidney in vivo under the diabetic condition. J Cell Mol Med 18:895–906

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li Y, Kimura T, Huyck RW, Laity JH, Andrews GK (2008) Zinc-induced formation of a coactivator complex containing the zinc-sensing transcription factor MTF-1, p300/CBP, and Sp1. Mol Cell Biol 28:4275–4284

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lichtlen P, Schaffner W (2001) Putting its fingers on stressful situations: the heavy metal-regulatory transcription factor MTF-1. BioEssays 23:1010–1017

    Article  PubMed  CAS  Google Scholar 

  • Lichtlen P, Wang Y, Belser T, Georgiev O, Certa U, Sack R, Schaffner W (2001) Target gene search for the metal-responsive transcription factor MTF-1. Nucleic Acids Res 29:1514–1523

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lindert U, Cramer M, Meuli M, Georgiev O, Schaffner W (2009) Metal-responsive transcription factor 1 (MTF-1) activity is regulated by a nonconventional nuclear localization signal and a metal-responsive transactivation domain. Mol Cell Biol 29:6283–6293

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lindert U, Leuzinger L, Steiner K, Georgiev O, Schaffner W (2008) Characterization of metal-responsive transcription factor (MTF-1) from the giant rodent capybara reveals features in common with human as well as with small rodents (Mouse, Rat). Short Communication. Chem Biodivers 5:1485–1494

    Article  PubMed  CAS  Google Scholar 

  • Maur AAd, Belser T, Elgar G, Georgiev O, Schaffner W (1999) Characterization of the transcription factor MTF-1 from the Japanese Pufferfish Fugu rubripes reveals evolutionary conservation of heavy metal stress response. Biol Chem 380:175–185

    Article  Google Scholar 

  • Murphy BJ, Kimura T, Sato BG, Shi Y, Andrews GK (2008) Metallothionein induction by hypoxia involves cooperative interactions between metal-responsive transcription factor-1 and hypoxia-inducible transcription factor-1α. Mol Cancer Res 6:483–490

    Article  PubMed  CAS  Google Scholar 

  • Murphy BJ, Sato BG, Dalton TP, Laderoute KR (2005) The metal-responsive transcription factor-1 contributes to HIF-1 activation during hypoxic stress. Biochem Biophys Res Commun 337:860–867

    Article  PubMed  CAS  Google Scholar 

  • Muse GW, Gilchrist DA, Nechaev S, Shah R, Parker JS, Grissom SF, Zeitlinger J, Adelman K (2007) RNA polymerase is poised for activation across the genome. Nat Genet 39:1507–1511

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ogra Y, Suzuki K, Gong P, Otsuka F, Koizumi S (2001) Negative regulatory role of Sp1 in metal responsive element-mediated transcriptional activation. J Biol Chem 276:16534–16539

    Article  PubMed  CAS  Google Scholar 

  • O’Halloran T (1993) Transition metals in control of gene expression. Science 261:715–725

    Article  PubMed  Google Scholar 

  • Okumura F, Li Y, Itoh N, Nakanishi T, Isobe M, Andrews GK, Kimura T (2011) The zinc-sensing transcription factor MTF-1 mediates zinc-induced epigenetic changes in chromatin of the mouse metallothionein-I promoter. Biochim Biophys Acta 1809:56–62

    Article  PubMed  CAS  Google Scholar 

  • Robinson JT, Thorvaldsdóttir H, Winckler W, Guttman M, Lander ES, Getz G, Mesirov JP (2011) Integrative genomics viewer. Nat Biotechnol 29:24

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Saydam N, Adams TK, Steiner F, Schaffner W, Freedman JH (2002) Regulation of metallothionein transcription by the metal-responsive transcription factor MTF-1—identification of signal transduction cascades that control metal-inducible transcription. J Biol Chem 277:20438–20445

    Article  PubMed  CAS  Google Scholar 

  • Saydam N, Georgiev O, Nakano MY, Greber UF, Schaffner W (2001) Nucleo-cytoplasmic trafficking of metal-regulatory transcription factor 1 Is regulated by diverse stress signals. J Biol Chem 276:25487–25495

    Article  PubMed  CAS  Google Scholar 

  • Schneider TD, Stephens RM (1990) Sequence logos: a new way to display consensus sequences. Nucleic Acids Res 18:6097–6100

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Selvaraj A, Balamurugan K, Yepiskoposyan H, Zhou H, Egli D, Georgiev O, Thiele DJ, Schaffner W (2005) Metal-responsive transcription factor (MTF-1) handles both extremes, copper load and copper starvation, by activating different genes. Gene Dev 19:891–896

    Article  PubMed  CAS  Google Scholar 

  • Sims HI, Chirn G-W, Marr MT (2012) Single nucleotide in the MTF-1 binding site can determine metal-specific transcription activation. Proc Natl Acad Sci USA 109:16516–16521

    Article  PubMed  Google Scholar 

  • Smirnova IV, Bittel DC, Ravindra R, Jiang H, Andrews GK (2000) Zinc and cadmium can promote rapid nuclear translocation of metal response element-binding transcription factor-1. J Biol Chem 275:9377–9384

    Article  PubMed  CAS  Google Scholar 

  • Stergachis AB, Haugen E, Shafer A, Fu W, Vernot B, Reynolds A, Raubitschek A, Ziegler S, LeProust EM, Akey JM, Stamatoyannopoulos JA (2013) Exonic transcription factor binding directs codon choice and affects protein evolution. Science 342:1367–1372

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stoytcheva ZR, Vladimirov V, Douet V, Stoychev I, Berry MJ (2010) Metal transcription factor-1 regulation via MREs in the transcribed regions of selenoprotein H and other metal-responsive genes. Biochim Biophys Acta 1800:416–424

    Article  PubMed  CAS  Google Scholar 

  • Stuart GW, Searle PF, Chen HY, Brinster RL, Palmiter RD (1984) A 12-base-pair DNA motif that is repeated several times in metallothionein gene promoters confers metal regulation to a heterologous gene. Proc Natl Acad Sci USA 81:7318–7322

    Article  PubMed  CAS  Google Scholar 

  • Thorvaldsdóttir H, Robinson JT, Mesirov JP (2013) Integrative genomics viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform 14:178–192

    Article  PubMed  CAS  Google Scholar 

  • Troadec M-B, Ward DM, Lo E, Kaplan J, De Domenico I (2010) Induction of FPN1 transcription by MTF-1 reveals a role for ferroportin in transition metal efflux. Blood 116:4657–4664

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Van Loo KMJ, Schaub C, Pitsch J, Kulbida R, Opitz T, Ekstein D, Dalal A, Urbach H, Beck H, Yaari Y, Schoch S, Becker AJ (2015) Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1. Nat Commun 6:8688

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang Y, Wimmer U, Lichtlen P, Inderbitzin D, Stieger B, Meier PJ, Hunziker L, Stallmach T, Forrer R, Rülicke T, Georgiev O, Schaffner W (2004) Metal-responsive transcription factor-1 (MTF-1) is essential for embryonic liver development and heavy metal detoxification in the adult liver. FASEB J 18:1071–1079

    Article  PubMed  CAS  Google Scholar 

  • Woringer M, Darzacq X, Izeddin I (2014) Geometry of the nucleus: a perspective on gene expression regulation. Curr Opin Chem Biol 20:112–119

    Article  PubMed  CAS  Google Scholar 

  • Xing K, He X (2015) Reassessing the “Duon” hypothesis of protein evolution. Mol Biol Evol 32:1056–1062

    Article  PubMed  CAS  Google Scholar 

  • Zhang B, Egli D, Georgiev O, Schaffner W (2001) The drosophila homolog of mammalian zinc finger factor MTF-1 activates transcription in response to heavy metals. Mol Cell Biol 21:4505–4514

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zheng D, Feeney GP, Kille P, Hogstrand C (2008) Regulation of ZIP and ZnT zinc transporters in zebrafish gill: zinc repression of ZIP10 transcription by an intronic MRE cluster. Physiol Genomics 34:205–214

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

This research was partially funded by the University of Georgia Experiment Station Hatch Funds (to AG).

Author information

Authors and Affiliations

  1. Department of Foods and Nutrition, University of Georgia, Athens, GA, USA

    Michael Francis & Arthur Grider

Authors
  1. Michael Francis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arthur Grider
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arthur Grider.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (XLSX 15 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Francis, M., Grider, A. Bioinformatic analysis of the metal response element and zinc-dependent gene regulation via the metal response element-binding transcription factor 1 in Caco-2 cells. Biometals 31, 639–646 (2018). https://doi.org/10.1007/s10534-018-0115-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-018-0115-5

Keywords

Search

Navigation