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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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Statistical DNA profiles (SDP) of nucleosome occupancy, Isw2(K215R) ChIP, Rap1p DIP, Rsc8p ChIP & transcriptome tiling array datasets.SDP were constructed as desribed for Figure 4. Figure 1C provides a color legend. Only results for consensus clusters are shown here, see Figure S11 for background clusters. Nucleosome occupancy data from 5A: tiling array dataset in 4 bp resolution [36]; 5B: Isw2(K215R) ChIP-tiling array data in 5 bp resolution [40]. 5D: transcriptome tiling array data in 8 bp resolution [68] on the sense strand; 5E: same as 5D but for the signal from the antisense strand. 5C & 5F: data are from [41] with resolution & SDP bin size: 32 bp; 5C: Rsc8-TAP ChIP-chip data in wildtype cells. 5F: Rap1 DIP-chip data (in vitro “DNA immunoprecipitation-chip” of genomic DNA by Rap1p).
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pone-0037906-g005: Statistical DNA profiles (SDP) of nucleosome occupancy, Isw2(K215R) ChIP, Rap1p DIP, Rsc8p ChIP & transcriptome tiling array datasets.SDP were constructed as desribed for Figure 4. Figure 1C provides a color legend. Only results for consensus clusters are shown here, see Figure S11 for background clusters. Nucleosome occupancy data from 5A: tiling array dataset in 4 bp resolution [36]; 5B: Isw2(K215R) ChIP-tiling array data in 5 bp resolution [40]. 5D: transcriptome tiling array data in 8 bp resolution [68] on the sense strand; 5E: same as 5D but for the signal from the antisense strand. 5C & 5F: data are from [41] with resolution & SDP bin size: 32 bp; 5C: Rsc8-TAP ChIP-chip data in wildtype cells. 5F: Rap1 DIP-chip data (in vitro “DNA immunoprecipitation-chip” of genomic DNA by Rap1p).

Mentions: Eukaryotic transcription appears to be initiated at NDR [36]. Nucleosome occupancy measurements take a population average, and nucleosomes that have a stable position in many cells give a pronounced signal with shorter distances between adjacent nucleosomes and are often denoted as “well-positioned”, while “fuzzy” positioning refers to a shallower signal with longer distances. Promoters are either found depleted of or occupied by nucleosomes in a given measurement. Four different types of promoter nucleosome configurations were distinguished by k-means clustering of nucleosome profiles around transcription start sites (TSS) [36], and we find highly significant enrichment of clusters with these gene types (Figure 2D). This enrichment can also be clearly seen in a heatmap of nucleosome occupancy data sorted by cluster genes and aligned at TSS, and in position-dependent Statistical DNA Profiles (SDP) of the same dataset (Figures 4 & 5A). Similar patterns can be seen in several other of nucleosome occupancy datasets [37], [40], [65] (Figure S12). Cluster A & C are clearly enriched with genes with wide and narrow NDR, respectively. Both of these classes have arrays of very well-positioned nucleosomes upstream and downstream [36]. Cluster AB genes are strongly depleted of nucleosomes in promoter and downstream regions, and this may result from the very high transcriptional frequencies (Figure S7A) of ribosomal protein genes [36]. Such genes are also significantly enriched in clusters B, B.C & B.D, but at a low percentage (Figure 2D). The heatmap (Figure 4) and statistical profiles (Figure 5A) show that these clusters additionally contain genes with a higher nucleosome occupancy at the promoter, a property shared with clusters B.D & D. Lastly, clusters B.D & D are enriched with genes that are characterized by a fuzzy nucleosome positioning. Thus, a gene classification based solely on the nucleosome configurations around the TSS distinguishes the ribosomal clusters A & C, from metabolic clusters B & D. Moreover, specific properties, such as promoter occupancy, NDR-size and stability of nucleosome positioning, differentiates between the anabolic and catabolic superclusters.


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

Machné R, Murray DB - PLoS ONE (2012)

Statistical DNA profiles (SDP) of nucleosome occupancy, Isw2(K215R) ChIP, Rap1p DIP, Rsc8p ChIP & transcriptome tiling array datasets.SDP were constructed as desribed for Figure 4. Figure 1C provides a color legend. Only results for consensus clusters are shown here, see Figure S11 for background clusters. Nucleosome occupancy data from 5A: tiling array dataset in 4 bp resolution [36]; 5B: Isw2(K215R) ChIP-tiling array data in 5 bp resolution [40]. 5D: transcriptome tiling array data in 8 bp resolution [68] on the sense strand; 5E: same as 5D but for the signal from the antisense strand. 5C & 5F: data are from [41] with resolution & SDP bin size: 32 bp; 5C: Rsc8-TAP ChIP-chip data in wildtype cells. 5F: Rap1 DIP-chip data (in vitro “DNA immunoprecipitation-chip” of genomic DNA by Rap1p).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3369881&req=5

pone-0037906-g005: Statistical DNA profiles (SDP) of nucleosome occupancy, Isw2(K215R) ChIP, Rap1p DIP, Rsc8p ChIP & transcriptome tiling array datasets.SDP were constructed as desribed for Figure 4. Figure 1C provides a color legend. Only results for consensus clusters are shown here, see Figure S11 for background clusters. Nucleosome occupancy data from 5A: tiling array dataset in 4 bp resolution [36]; 5B: Isw2(K215R) ChIP-tiling array data in 5 bp resolution [40]. 5D: transcriptome tiling array data in 8 bp resolution [68] on the sense strand; 5E: same as 5D but for the signal from the antisense strand. 5C & 5F: data are from [41] with resolution & SDP bin size: 32 bp; 5C: Rsc8-TAP ChIP-chip data in wildtype cells. 5F: Rap1 DIP-chip data (in vitro “DNA immunoprecipitation-chip” of genomic DNA by Rap1p).
Mentions: Eukaryotic transcription appears to be initiated at NDR [36]. Nucleosome occupancy measurements take a population average, and nucleosomes that have a stable position in many cells give a pronounced signal with shorter distances between adjacent nucleosomes and are often denoted as “well-positioned”, while “fuzzy” positioning refers to a shallower signal with longer distances. Promoters are either found depleted of or occupied by nucleosomes in a given measurement. Four different types of promoter nucleosome configurations were distinguished by k-means clustering of nucleosome profiles around transcription start sites (TSS) [36], and we find highly significant enrichment of clusters with these gene types (Figure 2D). This enrichment can also be clearly seen in a heatmap of nucleosome occupancy data sorted by cluster genes and aligned at TSS, and in position-dependent Statistical DNA Profiles (SDP) of the same dataset (Figures 4 & 5A). Similar patterns can be seen in several other of nucleosome occupancy datasets [37], [40], [65] (Figure S12). Cluster A & C are clearly enriched with genes with wide and narrow NDR, respectively. Both of these classes have arrays of very well-positioned nucleosomes upstream and downstream [36]. Cluster AB genes are strongly depleted of nucleosomes in promoter and downstream regions, and this may result from the very high transcriptional frequencies (Figure S7A) of ribosomal protein genes [36]. Such genes are also significantly enriched in clusters B, B.C & B.D, but at a low percentage (Figure 2D). The heatmap (Figure 4) and statistical profiles (Figure 5A) show that these clusters additionally contain genes with a higher nucleosome occupancy at the promoter, a property shared with clusters B.D & D. Lastly, clusters B.D & D are enriched with genes that are characterized by a fuzzy nucleosome positioning. Thus, a gene classification based solely on the nucleosome configurations around the TSS distinguishes the ribosomal clusters A & C, from metabolic clusters B & D. Moreover, specific properties, such as promoter occupancy, NDR-size and stability of nucleosome positioning, differentiates between the anabolic and catabolic superclusters.

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