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Transcriptomic response of yeast cells to ATX1 deletion under different copper levels.

Cankorur-Cetinkaya A, Eraslan S, Kirdar B - BMC Genomics (2016)

Bottom Line: ATX1 deletants were allowed to recover full respiratory capacity in the presence of excess copper in growth environment.The present finding revealed the dispensability of Atx1p for the transfer of copper ions to Ccc2p and highlighted its possible role in the cell cycle regulation.The results also showed the potential of Saccharomyces cerevisiae as a model organism in studying the capacity of ATOX1 as a therapeutic target for lung cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, Faculty of Engineering, Bogazici University, 34342, Istanbul, Turkey. ayca.cankorur@boun.edu.tr.

ABSTRACT

Background: Iron and copper homeostatic pathways are tightly linked since copper is required as a cofactor for high affinity iron transport. Atx1p plays an important role in the intracellular copper transport as a copper chaperone transferring copper from the transporters to Ccc2p for its subsequent insertion into Fet3p, which is required for high affinity iron transport.

Results: In this study, genome-wide transcriptional landscape of ATX1 deletants grown in media either lacking copper or having excess copper was investigated. ATX1 deletants were allowed to recover full respiratory capacity in the presence of excess copper in growth environment. The present study revealed that iron ion homeostasis was not significantly affected by the absence of ATX1 either at the transcriptional or metabolic levels, suggesting other possible roles for Atx1p in addition to its function as a chaperone in copper-dependent iron absorption. The analysis of the transcriptomic response of atx1∆/atx1∆ and its integration with the genetic interaction network highlighted for the first time, the possible role of ATX1 in cell cycle regulation, likewise its mammalian counterpart ATOX1, which was reported to play an important role in the copper-stimulated proliferation of non-small lung cancer cells.

Conclusions: The present finding revealed the dispensability of Atx1p for the transfer of copper ions to Ccc2p and highlighted its possible role in the cell cycle regulation. The results also showed the potential of Saccharomyces cerevisiae as a model organism in studying the capacity of ATOX1 as a therapeutic target for lung cancer therapy.

No MeSH data available.


Related in: MedlinePlus

Significantly and differentially expressed genes identified within each group. The figure contains the heat map representation of the genes, which were significantly and differentially expressed in response gene deletion, changing copper levels, or their additive effect, or their interactive effect. Colour key from blue to red indicates the low to high level of expression, respectively. These genes were further grouped according to the change in the direction of expression level. The number of the genes, which were identified to be up- or down-regulated in response to gene deletion effect or high copper levels were shown next to each group. Similarly, the number of the genes within each subgroup of G3, which compose of the genes significantly and differently expressed both in response to the gene deletion and copper level and the number of the genes within each cluster of G4, which compose of the genes significantly and differently expressed both in response to the interaction effect of gene deletion and copper level were represented next to each subgroup and cluster
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Fig1: Significantly and differentially expressed genes identified within each group. The figure contains the heat map representation of the genes, which were significantly and differentially expressed in response gene deletion, changing copper levels, or their additive effect, or their interactive effect. Colour key from blue to red indicates the low to high level of expression, respectively. These genes were further grouped according to the change in the direction of expression level. The number of the genes, which were identified to be up- or down-regulated in response to gene deletion effect or high copper levels were shown next to each group. Similarly, the number of the genes within each subgroup of G3, which compose of the genes significantly and differently expressed both in response to the gene deletion and copper level and the number of the genes within each cluster of G4, which compose of the genes significantly and differently expressed both in response to the interaction effect of gene deletion and copper level were represented next to each subgroup and cluster

Mentions: Genome-wide transcript levels of the ATX1 deleted and the reference strain obtained under conditions containing two different levels of copper were analysed by 2-way ANOVA to identify the significantly expressed genes and by fold change analysis to identify the differentially expressed genes (Additional file 4). The genes, which show both significant and differential change, were classified into four groups (G1-G4) and further investigated (Fig. 1). This analysis revealed that 210 genes (116 down- and 94 up-regulated) showed both significant and differential expression only in response to deletion of ATX1 gene when compared to the reference strain under both copper deficient and high levels of copper containing conditions (G1). A total of 733 genes (337 down- and 396 up-regulated) were differentially and significantly transcribed, in response to high copper levels (G2). G3 consisted of 106 genes, which showed differential and significant change both in response to gene deletion and change in the copper level without a significant interaction effect. This group of genes could further be classified into four different sub-groups; 57 genes (G3.1), which were down-regulated in response to the deletion of ATX1 when compared to the reference strain under both copper levels and up-regulated in response to high copper levels in comparison to the copper deficient conditions in both strains, 17 genes (G3.2), which were down-regulated both in the ATX1 deleted cells in comparison to the reference strain under both copper levels and under high copper containing conditions in comparison to the copper deficient conditions in both strains, 22 genes (G3.3), which were up-regulated both in the ATX1 deleted cells in comparison to the reference strain under both copper levels and under high copper containing conditions in comparison to the copper deficient condition in both strains, and 10 genes (G3.4), which showed higher expression in the ATX1 deleted cells compared to the reference strain under both copper levels and showed lower expression under high copper containing conditions when compared to the copper deficient conditions in both strains. The last group of genes (G4) consisted of 305 genes displaying a significant interaction effect and differential expression either in response to changing copper levels in any strain or in response to deletion of ATX1 under any condition. The expression profiles of these genes were used to cluster these genes into 6 different clusters using Self Organizing Maps (SOM) [18] and each cluster was separately investigated. Cluster 0 composed of the genes, which showed lower level of expression under conditions containing high copper levels compared to copper deficient conditions and this response was more pronounced in the ATX1 deleted cells. Cluster 1 contained the genes, which showed lower levels of expression under conditions containing high levels of copper when compared to copper deficient conditions in the ATX1 deleted cells but higher levels of expression in the reference strain. Cluster 2 composed of the genes, which were down-regulated in the absence of ATX1 gene under copper deficient conditions in comparison to the reference strain, but not responsive under high copper containing conditions. The genes, which showed the lower level of expression in the reference strain under high levels of copper containing conditions and higher level of expression in the ATX1 deleted strain under copper deficient conditions were clustered in Cluster 3. The genes in Cluster 4 were the ones that showed higher expression under high levels of copper containing condition when compared to the copper deficient conditions in the absence of ATX1 deleted cells but not in the reference strain. Lastly, the genes that were up-regulated under copper deficient conditions but down-regulated under high levels of copper containing conditions in the ATX1 deleted cells when compared to the reference strain were clustered in Cluster 5.Fig. 1


Transcriptomic response of yeast cells to ATX1 deletion under different copper levels.

Cankorur-Cetinkaya A, Eraslan S, Kirdar B - BMC Genomics (2016)

Significantly and differentially expressed genes identified within each group. The figure contains the heat map representation of the genes, which were significantly and differentially expressed in response gene deletion, changing copper levels, or their additive effect, or their interactive effect. Colour key from blue to red indicates the low to high level of expression, respectively. These genes were further grouped according to the change in the direction of expression level. The number of the genes, which were identified to be up- or down-regulated in response to gene deletion effect or high copper levels were shown next to each group. Similarly, the number of the genes within each subgroup of G3, which compose of the genes significantly and differently expressed both in response to the gene deletion and copper level and the number of the genes within each cluster of G4, which compose of the genes significantly and differently expressed both in response to the interaction effect of gene deletion and copper level were represented next to each subgroup and cluster
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4940881&req=5

Fig1: Significantly and differentially expressed genes identified within each group. The figure contains the heat map representation of the genes, which were significantly and differentially expressed in response gene deletion, changing copper levels, or their additive effect, or their interactive effect. Colour key from blue to red indicates the low to high level of expression, respectively. These genes were further grouped according to the change in the direction of expression level. The number of the genes, which were identified to be up- or down-regulated in response to gene deletion effect or high copper levels were shown next to each group. Similarly, the number of the genes within each subgroup of G3, which compose of the genes significantly and differently expressed both in response to the gene deletion and copper level and the number of the genes within each cluster of G4, which compose of the genes significantly and differently expressed both in response to the interaction effect of gene deletion and copper level were represented next to each subgroup and cluster
Mentions: Genome-wide transcript levels of the ATX1 deleted and the reference strain obtained under conditions containing two different levels of copper were analysed by 2-way ANOVA to identify the significantly expressed genes and by fold change analysis to identify the differentially expressed genes (Additional file 4). The genes, which show both significant and differential change, were classified into four groups (G1-G4) and further investigated (Fig. 1). This analysis revealed that 210 genes (116 down- and 94 up-regulated) showed both significant and differential expression only in response to deletion of ATX1 gene when compared to the reference strain under both copper deficient and high levels of copper containing conditions (G1). A total of 733 genes (337 down- and 396 up-regulated) were differentially and significantly transcribed, in response to high copper levels (G2). G3 consisted of 106 genes, which showed differential and significant change both in response to gene deletion and change in the copper level without a significant interaction effect. This group of genes could further be classified into four different sub-groups; 57 genes (G3.1), which were down-regulated in response to the deletion of ATX1 when compared to the reference strain under both copper levels and up-regulated in response to high copper levels in comparison to the copper deficient conditions in both strains, 17 genes (G3.2), which were down-regulated both in the ATX1 deleted cells in comparison to the reference strain under both copper levels and under high copper containing conditions in comparison to the copper deficient conditions in both strains, 22 genes (G3.3), which were up-regulated both in the ATX1 deleted cells in comparison to the reference strain under both copper levels and under high copper containing conditions in comparison to the copper deficient condition in both strains, and 10 genes (G3.4), which showed higher expression in the ATX1 deleted cells compared to the reference strain under both copper levels and showed lower expression under high copper containing conditions when compared to the copper deficient conditions in both strains. The last group of genes (G4) consisted of 305 genes displaying a significant interaction effect and differential expression either in response to changing copper levels in any strain or in response to deletion of ATX1 under any condition. The expression profiles of these genes were used to cluster these genes into 6 different clusters using Self Organizing Maps (SOM) [18] and each cluster was separately investigated. Cluster 0 composed of the genes, which showed lower level of expression under conditions containing high copper levels compared to copper deficient conditions and this response was more pronounced in the ATX1 deleted cells. Cluster 1 contained the genes, which showed lower levels of expression under conditions containing high levels of copper when compared to copper deficient conditions in the ATX1 deleted cells but higher levels of expression in the reference strain. Cluster 2 composed of the genes, which were down-regulated in the absence of ATX1 gene under copper deficient conditions in comparison to the reference strain, but not responsive under high copper containing conditions. The genes, which showed the lower level of expression in the reference strain under high levels of copper containing conditions and higher level of expression in the ATX1 deleted strain under copper deficient conditions were clustered in Cluster 3. The genes in Cluster 4 were the ones that showed higher expression under high levels of copper containing condition when compared to the copper deficient conditions in the absence of ATX1 deleted cells but not in the reference strain. Lastly, the genes that were up-regulated under copper deficient conditions but down-regulated under high levels of copper containing conditions in the ATX1 deleted cells when compared to the reference strain were clustered in Cluster 5.Fig. 1

Bottom Line: ATX1 deletants were allowed to recover full respiratory capacity in the presence of excess copper in growth environment.The present finding revealed the dispensability of Atx1p for the transfer of copper ions to Ccc2p and highlighted its possible role in the cell cycle regulation.The results also showed the potential of Saccharomyces cerevisiae as a model organism in studying the capacity of ATOX1 as a therapeutic target for lung cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, Faculty of Engineering, Bogazici University, 34342, Istanbul, Turkey. ayca.cankorur@boun.edu.tr.

ABSTRACT

Background: Iron and copper homeostatic pathways are tightly linked since copper is required as a cofactor for high affinity iron transport. Atx1p plays an important role in the intracellular copper transport as a copper chaperone transferring copper from the transporters to Ccc2p for its subsequent insertion into Fet3p, which is required for high affinity iron transport.

Results: In this study, genome-wide transcriptional landscape of ATX1 deletants grown in media either lacking copper or having excess copper was investigated. ATX1 deletants were allowed to recover full respiratory capacity in the presence of excess copper in growth environment. The present study revealed that iron ion homeostasis was not significantly affected by the absence of ATX1 either at the transcriptional or metabolic levels, suggesting other possible roles for Atx1p in addition to its function as a chaperone in copper-dependent iron absorption. The analysis of the transcriptomic response of atx1∆/atx1∆ and its integration with the genetic interaction network highlighted for the first time, the possible role of ATX1 in cell cycle regulation, likewise its mammalian counterpart ATOX1, which was reported to play an important role in the copper-stimulated proliferation of non-small lung cancer cells.

Conclusions: The present finding revealed the dispensability of Atx1p for the transfer of copper ions to Ccc2p and highlighted its possible role in the cell cycle regulation. The results also showed the potential of Saccharomyces cerevisiae as a model organism in studying the capacity of ATOX1 as a therapeutic target for lung cancer therapy.

No MeSH data available.


Related in: MedlinePlus