Global Transcriptome and Deletome Profiles of Yeast Exposed to Transition Metals

Abstract

A variety of pathologies are associated with exposure to supraphysiological concentrations of essential metals and to non-essential metals and metalloids. The molecular mechanisms linking metal exposure to human pathologies have not been clearly defined. To address these gaps in our understanding of the molecular biology of transition metals, the genomic effects of exposure to Group IB (copper, silver), IIB (zinc, cadmium, mercury), VIA (chromium), and VB (arsenic) elements on the yeast Saccharomyces cerevisiae were examined. Two comprehensive sets of metal-responsive genomic profiles were generated following exposure to equi-toxic concentrations of metal: one that provides information on the transcriptional changes associated with metal exposure (transcriptome), and a second that provides information on the relationship between the expression of ∼4,700 non-essential genes and sensitivity to metal exposure (deletome). Approximately 22% of the genome was affected by exposure to at least one metal. Principal component and cluster analyses suggest that the chemical properties of the metal are major determinants in defining the expression profile. Furthermore, cells may have developed common or convergent regulatory mechanisms to accommodate metal exposure. The transcriptome and deletome had 22 genes in common, however, comparison between Gene Ontology biological processes for the two gene sets revealed that metal stress adaptation and detoxification categories were commonly enriched. Analysis of the transcriptome and deletome identified several evolutionarily conserved, signal transduction pathways that may be involved in regulating the responses to metal exposure. In this study, we identified genes and cognate signaling pathways that respond to exposure to essential and non-essential metals. In addition, genes that are essential for survival in the presence of these metals were identified. This information will contribute to our understanding of the molecular mechanism by which organisms respond to metal stress, and could lead to an understanding of the connection between environmental stress and signal transduction pathways.

Author Summary

Environmental and human health threats are posed by contamination from transition metals. A variety of pathologies are associated with exposure to supraphysiological concentrations of essential metals and to non-essential metals and metalloids. To defend against metal toxicity, sophisticated defense mechanisms have evolved. Although many of the genes and regulatory pathways have been identified, the consequence of metal exposure on a systematic level has not been examined. To better define the mechanism involved in the metal response, we examined the effects of zinc, cadmium, mercury, copper, silver, chromium, and arsenic on gene expression in the yeast Saccharomyces cerevisiae. In addition, the roles of ∼4,500 non-essential genes in protecting yeast from metal toxicity were determined. Data analyses suggest that the chemical properties of the metal are major determinants in defining its biological effect on cells. Furthermore, cells may have developed common or convergent regulatory mechanisms to accommodate metal exposure. Several evolutionarily conserved regulatory pathways were identified that link metal exposure, disruption of normal metabolism and gene expression. These results provide a global understanding of the biological responses to metal exposure and the stress response.