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Yeast glucose pathways converge on the transcriptional regulation of trehalose biosynthesis.

Apweiler E, Sameith K, Margaritis T, Brabers N, van de Pasch L, Bakker LV, van Leenen D, Holstege FC, Kemmeren P - BMC Genomics (2012)

Bottom Line: In general, the mutations do not induce pathway-specific transcriptional responses.Epistasis analysis of tps2Δ double mutants supports this prediction.Although based on transcriptional changes only, these results suggest that all changes in perceived glucose levels ultimately lead to a shift in trehalose biosynthesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Utrecht, the Netherlands.

ABSTRACT

Background: Cellular glucose availability is crucial for the functioning of most biological processes. Our understanding of the glucose regulatory system has been greatly advanced by studying the model organism Saccharomyces cerevisiae, but many aspects of this system remain elusive. To understand the organisation of the glucose regulatory system, we analysed 91 deletion mutants of the different glucose signalling and metabolic pathways in Saccharomyces cerevisiae using DNA microarrays.

Results: In general, the mutations do not induce pathway-specific transcriptional responses. Instead, one main transcriptional response is discerned, which varies in direction to mimic either a high or a low glucose response. Detailed analysis uncovers established and new relationships within and between individual pathways and their members. In contrast to signalling components, metabolic components of the glucose regulatory system are transcriptionally more frequently affected. A new network approach is applied that exposes the hierarchical organisation of the glucose regulatory system.

Conclusions: The tight interconnection between the different pathways of the glucose regulatory system is reflected by the main transcriptional response observed. Tps2 and Tsl1, two enzymes involved in the biosynthesis of the storage carbohydrate trehalose, are predicted to be the most downstream transcriptional components. Epistasis analysis of tps2Δ double mutants supports this prediction. Although based on transcriptional changes only, these results suggest that all changes in perceived glucose levels ultimately lead to a shift in trehalose biosynthesis.

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Hierarchical network reconstruction. Tps2 is the most downstream transcriptional component. (A) Possible data observations. A blue edge from x to y indicates decreased transcription of y in the deletion of x, a yellow edge indicates increased transcription. Edges of the same colour going from x and y to downstream target genes denote correlation between the gene expression profiles of xΔ and yΔ, anti-correlation otherwise. (B) Different types of data observations, as presented in (A), are exemplified. Dashed grey lines indicate 1.5 FC. Solid grey lines indicate the linear regression line fitted through the data points. Deletions of x and y are represented on the x- and y-axis respectively. The transcriptional change of y is highlighted by a red dot. (C) Data interpretations. The two leftmost types of data observations are interpreted as sequential relationships, in which transcriptional changes of downstream target genes observed in the deletion of x are indirect through the transcriptional regulation of y. The two rightmost types of data observations are interpreted as non-sequential relationships such as feedback from y to x itself or downstream target genes of x. (D) Unique edges (green and purple, solid and dashed) are used to denote the different types (L1, L2, F1 and F2, see Methods for details) of data observations in the network. (E) Data observations are summarised and represented as described in (D) for all components of the glucose regulatory system that upon deletion result in significant transcriptional changes compared to WT.
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Figure 5: Hierarchical network reconstruction. Tps2 is the most downstream transcriptional component. (A) Possible data observations. A blue edge from x to y indicates decreased transcription of y in the deletion of x, a yellow edge indicates increased transcription. Edges of the same colour going from x and y to downstream target genes denote correlation between the gene expression profiles of xΔ and yΔ, anti-correlation otherwise. (B) Different types of data observations, as presented in (A), are exemplified. Dashed grey lines indicate 1.5 FC. Solid grey lines indicate the linear regression line fitted through the data points. Deletions of x and y are represented on the x- and y-axis respectively. The transcriptional change of y is highlighted by a red dot. (C) Data interpretations. The two leftmost types of data observations are interpreted as sequential relationships, in which transcriptional changes of downstream target genes observed in the deletion of x are indirect through the transcriptional regulation of y. The two rightmost types of data observations are interpreted as non-sequential relationships such as feedback from y to x itself or downstream target genes of x. (D) Unique edges (green and purple, solid and dashed) are used to denote the different types (L1, L2, F1 and F2, see Methods for details) of data observations in the network. (E) Data observations are summarised and represented as described in (D) for all components of the glucose regulatory system that upon deletion result in significant transcriptional changes compared to WT.

Mentions: To further determine whether members of the metabolic pathways are indeed the most downstream transcriptional components, a new approach was applied to deduce the hierarchy of transcriptional regulation within the glucose regulatory system (see Methods). The approach is designed to explain a gene expression profile measured upon the deletion of one pathway member through the transcriptional regulation of another pathway member. Two measures are used to define the hierarchical relationship between two pathway members: (a) the transcript change they elicit on each other, and (b) the correlation of their gene expression profiles. Depending on the sign of these measures, four possible combinations are distinguished (Figure 5A, B) and categorised into two types (Figure 5C) “sequential” and “non-sequential”. A sequential relationship is observed when the transcript changes for a pathway member as a result of its deletion can be explained by the altered transcription of a second pathway member (Figure 5A-D, left). This is the case, for instance, when the transcript level of pathway member y is reduced upon the deletion of pathway member x, resulting in a gene expression profile highly similar to the deletion of y itself. In the reconstructed transcription network, pathway member y is hence placed downstream to pathway member x. On the other hand, gene expression profiles may indicate a non-sequential relationship, such as a feedback circuit between two pathway members (Figure 5A-D, right). In this case, the transcriptional regulation of one pathway member cannot easily explain the gene expression profile of the second pathway member, indicating a non-sequential relationship that involves additional intermediate components.


Yeast glucose pathways converge on the transcriptional regulation of trehalose biosynthesis.

Apweiler E, Sameith K, Margaritis T, Brabers N, van de Pasch L, Bakker LV, van Leenen D, Holstege FC, Kemmeren P - BMC Genomics (2012)

Hierarchical network reconstruction. Tps2 is the most downstream transcriptional component. (A) Possible data observations. A blue edge from x to y indicates decreased transcription of y in the deletion of x, a yellow edge indicates increased transcription. Edges of the same colour going from x and y to downstream target genes denote correlation between the gene expression profiles of xΔ and yΔ, anti-correlation otherwise. (B) Different types of data observations, as presented in (A), are exemplified. Dashed grey lines indicate 1.5 FC. Solid grey lines indicate the linear regression line fitted through the data points. Deletions of x and y are represented on the x- and y-axis respectively. The transcriptional change of y is highlighted by a red dot. (C) Data interpretations. The two leftmost types of data observations are interpreted as sequential relationships, in which transcriptional changes of downstream target genes observed in the deletion of x are indirect through the transcriptional regulation of y. The two rightmost types of data observations are interpreted as non-sequential relationships such as feedback from y to x itself or downstream target genes of x. (D) Unique edges (green and purple, solid and dashed) are used to denote the different types (L1, L2, F1 and F2, see Methods for details) of data observations in the network. (E) Data observations are summarised and represented as described in (D) for all components of the glucose regulatory system that upon deletion result in significant transcriptional changes compared to WT.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 5: Hierarchical network reconstruction. Tps2 is the most downstream transcriptional component. (A) Possible data observations. A blue edge from x to y indicates decreased transcription of y in the deletion of x, a yellow edge indicates increased transcription. Edges of the same colour going from x and y to downstream target genes denote correlation between the gene expression profiles of xΔ and yΔ, anti-correlation otherwise. (B) Different types of data observations, as presented in (A), are exemplified. Dashed grey lines indicate 1.5 FC. Solid grey lines indicate the linear regression line fitted through the data points. Deletions of x and y are represented on the x- and y-axis respectively. The transcriptional change of y is highlighted by a red dot. (C) Data interpretations. The two leftmost types of data observations are interpreted as sequential relationships, in which transcriptional changes of downstream target genes observed in the deletion of x are indirect through the transcriptional regulation of y. The two rightmost types of data observations are interpreted as non-sequential relationships such as feedback from y to x itself or downstream target genes of x. (D) Unique edges (green and purple, solid and dashed) are used to denote the different types (L1, L2, F1 and F2, see Methods for details) of data observations in the network. (E) Data observations are summarised and represented as described in (D) for all components of the glucose regulatory system that upon deletion result in significant transcriptional changes compared to WT.
Mentions: To further determine whether members of the metabolic pathways are indeed the most downstream transcriptional components, a new approach was applied to deduce the hierarchy of transcriptional regulation within the glucose regulatory system (see Methods). The approach is designed to explain a gene expression profile measured upon the deletion of one pathway member through the transcriptional regulation of another pathway member. Two measures are used to define the hierarchical relationship between two pathway members: (a) the transcript change they elicit on each other, and (b) the correlation of their gene expression profiles. Depending on the sign of these measures, four possible combinations are distinguished (Figure 5A, B) and categorised into two types (Figure 5C) “sequential” and “non-sequential”. A sequential relationship is observed when the transcript changes for a pathway member as a result of its deletion can be explained by the altered transcription of a second pathway member (Figure 5A-D, left). This is the case, for instance, when the transcript level of pathway member y is reduced upon the deletion of pathway member x, resulting in a gene expression profile highly similar to the deletion of y itself. In the reconstructed transcription network, pathway member y is hence placed downstream to pathway member x. On the other hand, gene expression profiles may indicate a non-sequential relationship, such as a feedback circuit between two pathway members (Figure 5A-D, right). In this case, the transcriptional regulation of one pathway member cannot easily explain the gene expression profile of the second pathway member, indicating a non-sequential relationship that involves additional intermediate components.

Bottom Line: In general, the mutations do not induce pathway-specific transcriptional responses.Epistasis analysis of tps2Δ double mutants supports this prediction.Although based on transcriptional changes only, these results suggest that all changes in perceived glucose levels ultimately lead to a shift in trehalose biosynthesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Utrecht, the Netherlands.

ABSTRACT

Background: Cellular glucose availability is crucial for the functioning of most biological processes. Our understanding of the glucose regulatory system has been greatly advanced by studying the model organism Saccharomyces cerevisiae, but many aspects of this system remain elusive. To understand the organisation of the glucose regulatory system, we analysed 91 deletion mutants of the different glucose signalling and metabolic pathways in Saccharomyces cerevisiae using DNA microarrays.

Results: In general, the mutations do not induce pathway-specific transcriptional responses. Instead, one main transcriptional response is discerned, which varies in direction to mimic either a high or a low glucose response. Detailed analysis uncovers established and new relationships within and between individual pathways and their members. In contrast to signalling components, metabolic components of the glucose regulatory system are transcriptionally more frequently affected. A new network approach is applied that exposes the hierarchical organisation of the glucose regulatory system.

Conclusions: The tight interconnection between the different pathways of the glucose regulatory system is reflected by the main transcriptional response observed. Tps2 and Tsl1, two enzymes involved in the biosynthesis of the storage carbohydrate trehalose, are predicted to be the most downstream transcriptional components. Epistasis analysis of tps2Δ double mutants supports this prediction. Although based on transcriptional changes only, these results suggest that all changes in perceived glucose levels ultimately lead to a shift in trehalose biosynthesis.

Show MeSH
Related in: MedlinePlus