Abstract
Zinc is essential for biological systems, and aberrant zinc metabolism is implicated in a broad range of human diseases. To maintain homeostasis in response to fluctuating levels of dietary zinc, animals regulate gene expression; however, mechanisms that mediate the transcriptional response to fluctuating levels of zinc have not been fully defined. Here, we identified DNA enhancer elements that mediate intestine-specific transcriptional activation in response to high levels of dietary zinc in C. elegans. Using bioinformatics, we characterized an evolutionarily conserved enhancer element present in multiple zinc-inducible genes, the high zinc activation (HZA) element. The HZA was consistently adjacent to a GATA element that mediates expression in intestinal cells. Functional studies using transgenic animals demonstrated that this modular system of DNA enhancers mediates tissue-specific transcriptional activation in response to high levels of dietary zinc. We used this information to search the genome and successfully identified novel zinc-inducible genes. To characterize the mechanism of enhancer function, we demonstrated that the GATA transcription factor ELT-2 and the mediator subunit MDT-15 are necessary for zinc-responsive transcriptional activation. These findings define new mechanisms of zinc homeostasis and tissue-specific regulation of transcription.
Highlights
Zinc is a metal that is essential in all biological systems
We identified an evolutionarily conserved DNA element that is present in the promoter regions of multiple genes that are induced by high dietary zinc, which we named the C. elegans high zinc activation (HZA) element
Supplementation with copper did not induce green fluorescent protein (GFP) protein expression. These results suggest that the cis-regulatory module composed of the HZA and GATA elements is sufficient to mediate transcriptional activation in intestinal cells in response to zinc and cadmium, but not to other metals, such as copper
Summary
Zinc is involved in a wide range of cellular processes; Zn2+ is a structural and/or enzymatic cofactor in a large number of proteins [1], and Zn2+ is a signaling molecule during development, immune responses and synaptic transmission [2,3,4]. Zinc is essential for human health, and abnormalities of zinc metabolism are implicated in several diseases. Zinc deficiency due to inadequate dietary intake or genetic disorders that disrupt zinc uptake causes a wide range of abnormalities in multiple tissues including the skin and immune system [5,6,7]. Genetic variations that affect zinc metabolism have been correlated with a variety of human diseases, such as cancer, diabetes and neurodegenerative diseases [10,11,12]. Understanding mechanisms that regulate zinc metabolism is important for biology and human health
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