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.

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.