Transcriptional remodelling in response to changing copper levels in the Wilson and Menkes disease model of Saccharomyces cerevisiae

Abstract

A high degree of conservation of the copper homeostasis pathway between yeast and humans makes yeast an ideal model organism for studying copper-related disorders. In this study, a system based integrative approach was used to investigate the genome-wide effects of the deletion of the yeast ortholog of Wilson and Menkes diseases encoding a Cu²⁺-transporting P-type ATPase (CCC2) in different copper containing media and to compare with the wild type. The experimental design applied in this study enabled the observation of the effect of CCC2 deletion, extracellular copper levels and interactive effects of both factors in S. cerevisiae cells. The integrative analysis of the transcriptome with the interactome and regulome further elucidated the pathways affected by the disturbance of copper homeostasis. The results demonstrated that iron homeostasis is disturbed in the absence of CCC2 under copper deficient conditions and also revealed the importance of this gene in the maintenance of iron homeostasis under high copper conditions. NAD⁺ metabolism was observed to be affected both by the deletion of CCC2 and the level of bio-available extracellular copper. The regulation of glucose transporters was also affected in the absence of CCC2 and a starvation-like response was observed in a copper level dependent manner. Alterations in the amino acid metabolism and specifically in the arginine metabolic process observed at the transcriptional level provided further support through the integration of the metabolomic data. This study also highlighted pyridoxine deficiency caused by the absence of CCC2. The observation of the improvement in the respiratory capacity of CCC2 deleted cells by supplementation with pyridoxine as well as with nicotinic acid may shed light on novel therapeutic interventions for Wilson and Menkes diseases.