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The yin and yang of yeast transcription: elements of a global feedback system between metabolism and chromatin.

Machné R, Murray DB - PLoS ONE (2012)

Bottom Line: We show that the ATP:ADP ratio oscillates, compatible with alternating metabolic activity of the two superclusters and differential feedback on their transcription via activating (RSC) and repressive (Isw2) types of promoter structure remodeling.We propose a novel feedback mechanism, where the energetic state of the cell, reflected in the ATP:ADP ratio, gates the transcription of large, but functionally coherent groups of genes via differential effects of ATP-dependent nucleosome remodeling machineries.Besides providing a mechanistic hypothesis for the delayed negative feedback that results in the oscillatory phenotype, this mechanism may underpin the continuous adaptation of growth to environmental conditions.

View Article: PubMed Central - PubMed

Affiliation: Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria. raim@tbi.univie.ac.at

ABSTRACT
When grown in continuous culture, budding yeast cells tend to synchronize their respiratory activity to form a stable oscillation that percolates throughout cellular physiology and involves the majority of the protein-coding transcriptome. Oscillations in batch culture and at single cell level support the idea that these dynamics constitute a general growth principle. The precise molecular mechanisms and biological functions of the oscillation remain elusive. Fourier analysis of transcriptome time series datasets from two different oscillation periods (0.7 h and 5 h) reveals seven distinct co-expression clusters common to both systems (34% of all yeast ORF), which consolidate into two superclusters when correlated with a compilation of 1,327 unrelated transcriptome datasets. These superclusters encode for cell growth and anabolism during the phase of high, and mitochondrial growth, catabolism and stress response during the phase of low oxygen uptake. The promoters of each cluster are characterized by different nucleotide contents, promoter nucleosome configurations, and dependence on ATP-dependent nucleosome remodeling complexes. We show that the ATP:ADP ratio oscillates, compatible with alternating metabolic activity of the two superclusters and differential feedback on their transcription via activating (RSC) and repressive (Isw2) types of promoter structure remodeling. We propose a novel feedback mechanism, where the energetic state of the cell, reflected in the ATP:ADP ratio, gates the transcription of large, but functionally coherent groups of genes via differential effects of ATP-dependent nucleosome remodeling machineries. Besides providing a mechanistic hypothesis for the delayed negative feedback that results in the oscillatory phenotype, this mechanism may underpin the continuous adaptation of growth to environmental conditions.

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Nucleotide content & in vitro nucleosome occupancy.Figure 1C provides a color legend. 8A & 8B: local GC- and purine frequencies were first calculated for each gene and each position in sliding windows (size: 71 nt.), and then SDP were constructed using t-tests for statistics visualization. Tests were performed without prior binning of values, and instead values are shown only for each 10th nucleotide position for visual clarity. 8C: in vitro nucleosome reconstitution at low histone levels [37], 1 bp resolution, SDP with bin size 10 bp and Mann-Whitney-Wilcoxon tests. Background clusters are shown in Figure S20.
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pone-0037906-g008: Nucleotide content & in vitro nucleosome occupancy.Figure 1C provides a color legend. 8A & 8B: local GC- and purine frequencies were first calculated for each gene and each position in sliding windows (size: 71 nt.), and then SDP were constructed using t-tests for statistics visualization. Tests were performed without prior binning of values, and instead values are shown only for each 10th nucleotide position for visual clarity. 8C: in vitro nucleosome reconstitution at low histone levels [37], 1 bp resolution, SDP with bin size 10 bp and Mann-Whitney-Wilcoxon tests. Background clusters are shown in Figure S20.

Mentions: Such a direct feedback between energetic state and gene expression is known from bacteria, where the ATP:ADP ratio correlates with the extent of negative supercoiling that is introduced by ATP-dependent gyrase [47], [48] which in turn differentially affects transcription of the gene encoding for the gyrase [81] and for anabolic and catabolic enzymes [50]. While in Escherichia coli the resulting feedback was interpreted in terms of a homeostatic regulation system, rhythmic changes in DNA structure were observed over the circadian cycle of the cyanobacterium Synechococcus elongatus PCC7942 [52]. Negative supercoiling is increased during the photosynthetic phase and is required for transcription from GC-rich genes [53]. In our system, all clusters are significantly enriched in one of four distinct promoter nucleosome configurations (Figures 2D & 5A) [36]. Nucleosome occupancy partially depends on sequence properties, e.g., the GC-content [38]. Cluster A transcripts are purine-rich and cluster D genes are GC-rich (Figures 8A & 8B). Thus, the clusters may differ in sequence-dependent “default” nucleosome configurations or overall occupancy, which is also reflected in the differential in vitro occupancy (Figure 8C) [37] and could lay the grounds for differential regulation. A candidate mechanism is ATP-dependent nucleosome remodeling, where ATP hydrolysis provides the mechanical force to generate negative superhelical torque [82] and break DNA-histone contacts [83]. The addition of ATP to naked DNA, histones and cell extract allowed the in vitro reconstitution of in vivo promoter nucleosome configurations, suggesting a major role of ATP-dependent remodeling in the establishment and maintenance of different types of promoter nucleosome configuration [43]. The differential consequences of promoter nucleosome remodeling by the RSC- and Isw2-types of remodeling machineries, and their differential association with cluster genes (Figures 2E, 5B, 5C, S5, S6 & S9) elegantly complement the proposed feedback model between anabolic and catabolic pathways (Figure 7C). At high ATP:ADP ratio, RSC would keep promoters of anabolic genes open and competent for transcription, while Isw2 would actively repress catabolic gene promoters. When the ATP:ADP ratio drops both remodelers may become less active, and gene expression would switch from growth to catabolic genes. ADP promotes the dissociation of Isw2 from DNA [84], further supporting a direct influence of the ATP:ADP ratio. In this scenario, ATP-dependent nucleosome remodeling literally gates gene expression by opening or closing promoter regions apt to the current energetic state of the cell. However, the diverse targets of RSC remain elusive and are difficult to establish experimentally [42]. Interestingly, the step-length of RSC-mediated remodeling, i.e., the distance over which a given nucleosome is moved along the DNA in one remodeling cycle, has recently been observed to depend on the ATP concentration in vitro[85], which in vivo could lead to differential rotational positioning, and thus exposure or covering, of regulatory motifs [86] such as the TATA-Box in the metabolic cohorts B and D of the two superclusters. Oscillating levels of acetyl-CoA- and SAGA-dependent histone acetylation have been found to enable rapid transcription of growth genes (clusters AB, B) in the oxidative phase, while the SAGA complex binds to stress-regulated genes (D) during the reductive phase of a 5 h oscillation [87]. Thus, RSC and SAGA, or ATP-dependent nucleosome remodeling and acetyl-CoA-dependent histone acetylation, may cooperate [88] at both anabolic and catabolic gene clusters, and relate the metabolic state of the cell to an appropriate transcriptional output.


The yin and yang of yeast transcription: elements of a global feedback system between metabolism and chromatin.

Machné R, Murray DB - PLoS ONE (2012)

Nucleotide content & in vitro nucleosome occupancy.Figure 1C provides a color legend. 8A & 8B: local GC- and purine frequencies were first calculated for each gene and each position in sliding windows (size: 71 nt.), and then SDP were constructed using t-tests for statistics visualization. Tests were performed without prior binning of values, and instead values are shown only for each 10th nucleotide position for visual clarity. 8C: in vitro nucleosome reconstitution at low histone levels [37], 1 bp resolution, SDP with bin size 10 bp and Mann-Whitney-Wilcoxon tests. Background clusters are shown in Figure S20.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3369881&req=5

pone-0037906-g008: Nucleotide content & in vitro nucleosome occupancy.Figure 1C provides a color legend. 8A & 8B: local GC- and purine frequencies were first calculated for each gene and each position in sliding windows (size: 71 nt.), and then SDP were constructed using t-tests for statistics visualization. Tests were performed without prior binning of values, and instead values are shown only for each 10th nucleotide position for visual clarity. 8C: in vitro nucleosome reconstitution at low histone levels [37], 1 bp resolution, SDP with bin size 10 bp and Mann-Whitney-Wilcoxon tests. Background clusters are shown in Figure S20.
Mentions: Such a direct feedback between energetic state and gene expression is known from bacteria, where the ATP:ADP ratio correlates with the extent of negative supercoiling that is introduced by ATP-dependent gyrase [47], [48] which in turn differentially affects transcription of the gene encoding for the gyrase [81] and for anabolic and catabolic enzymes [50]. While in Escherichia coli the resulting feedback was interpreted in terms of a homeostatic regulation system, rhythmic changes in DNA structure were observed over the circadian cycle of the cyanobacterium Synechococcus elongatus PCC7942 [52]. Negative supercoiling is increased during the photosynthetic phase and is required for transcription from GC-rich genes [53]. In our system, all clusters are significantly enriched in one of four distinct promoter nucleosome configurations (Figures 2D & 5A) [36]. Nucleosome occupancy partially depends on sequence properties, e.g., the GC-content [38]. Cluster A transcripts are purine-rich and cluster D genes are GC-rich (Figures 8A & 8B). Thus, the clusters may differ in sequence-dependent “default” nucleosome configurations or overall occupancy, which is also reflected in the differential in vitro occupancy (Figure 8C) [37] and could lay the grounds for differential regulation. A candidate mechanism is ATP-dependent nucleosome remodeling, where ATP hydrolysis provides the mechanical force to generate negative superhelical torque [82] and break DNA-histone contacts [83]. The addition of ATP to naked DNA, histones and cell extract allowed the in vitro reconstitution of in vivo promoter nucleosome configurations, suggesting a major role of ATP-dependent remodeling in the establishment and maintenance of different types of promoter nucleosome configuration [43]. The differential consequences of promoter nucleosome remodeling by the RSC- and Isw2-types of remodeling machineries, and their differential association with cluster genes (Figures 2E, 5B, 5C, S5, S6 & S9) elegantly complement the proposed feedback model between anabolic and catabolic pathways (Figure 7C). At high ATP:ADP ratio, RSC would keep promoters of anabolic genes open and competent for transcription, while Isw2 would actively repress catabolic gene promoters. When the ATP:ADP ratio drops both remodelers may become less active, and gene expression would switch from growth to catabolic genes. ADP promotes the dissociation of Isw2 from DNA [84], further supporting a direct influence of the ATP:ADP ratio. In this scenario, ATP-dependent nucleosome remodeling literally gates gene expression by opening or closing promoter regions apt to the current energetic state of the cell. However, the diverse targets of RSC remain elusive and are difficult to establish experimentally [42]. Interestingly, the step-length of RSC-mediated remodeling, i.e., the distance over which a given nucleosome is moved along the DNA in one remodeling cycle, has recently been observed to depend on the ATP concentration in vitro[85], which in vivo could lead to differential rotational positioning, and thus exposure or covering, of regulatory motifs [86] such as the TATA-Box in the metabolic cohorts B and D of the two superclusters. Oscillating levels of acetyl-CoA- and SAGA-dependent histone acetylation have been found to enable rapid transcription of growth genes (clusters AB, B) in the oxidative phase, while the SAGA complex binds to stress-regulated genes (D) during the reductive phase of a 5 h oscillation [87]. Thus, RSC and SAGA, or ATP-dependent nucleosome remodeling and acetyl-CoA-dependent histone acetylation, may cooperate [88] at both anabolic and catabolic gene clusters, and relate the metabolic state of the cell to an appropriate transcriptional output.

Bottom Line: We show that the ATP:ADP ratio oscillates, compatible with alternating metabolic activity of the two superclusters and differential feedback on their transcription via activating (RSC) and repressive (Isw2) types of promoter structure remodeling.We propose a novel feedback mechanism, where the energetic state of the cell, reflected in the ATP:ADP ratio, gates the transcription of large, but functionally coherent groups of genes via differential effects of ATP-dependent nucleosome remodeling machineries.Besides providing a mechanistic hypothesis for the delayed negative feedback that results in the oscillatory phenotype, this mechanism may underpin the continuous adaptation of growth to environmental conditions.

View Article: PubMed Central - PubMed

Affiliation: Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria. raim@tbi.univie.ac.at

ABSTRACT
When grown in continuous culture, budding yeast cells tend to synchronize their respiratory activity to form a stable oscillation that percolates throughout cellular physiology and involves the majority of the protein-coding transcriptome. Oscillations in batch culture and at single cell level support the idea that these dynamics constitute a general growth principle. The precise molecular mechanisms and biological functions of the oscillation remain elusive. Fourier analysis of transcriptome time series datasets from two different oscillation periods (0.7 h and 5 h) reveals seven distinct co-expression clusters common to both systems (34% of all yeast ORF), which consolidate into two superclusters when correlated with a compilation of 1,327 unrelated transcriptome datasets. These superclusters encode for cell growth and anabolism during the phase of high, and mitochondrial growth, catabolism and stress response during the phase of low oxygen uptake. The promoters of each cluster are characterized by different nucleotide contents, promoter nucleosome configurations, and dependence on ATP-dependent nucleosome remodeling complexes. We show that the ATP:ADP ratio oscillates, compatible with alternating metabolic activity of the two superclusters and differential feedback on their transcription via activating (RSC) and repressive (Isw2) types of promoter structure remodeling. We propose a novel feedback mechanism, where the energetic state of the cell, reflected in the ATP:ADP ratio, gates the transcription of large, but functionally coherent groups of genes via differential effects of ATP-dependent nucleosome remodeling machineries. Besides providing a mechanistic hypothesis for the delayed negative feedback that results in the oscillatory phenotype, this mechanism may underpin the continuous adaptation of growth to environmental conditions.

Show MeSH
Related in: MedlinePlus