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
- 113 Downloads
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.
KeywordsMTF-1 MRE Zinc Nutrigenomics Transcription factor
This research was partially funded by the University of Georgia Experiment Station Hatch Funds (to AG).
- 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 20:1114–1122CrossRefPubMedPubMedCentralGoogle Scholar
- Bembom O (2017) seqLogo: sequence logos for DNA sequence alignments. R package version 1.44.0Google 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 4:1042Google 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 8:337–343CrossRefPubMedGoogle 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 28:1647–1649CrossRefPubMedPubMedCentralGoogle 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 5:1485–1494CrossRefPubMedGoogle 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 277:20438–20445CrossRefPubMedGoogle 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 18:1071–1079CrossRefPubMedGoogle Scholar