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Transcriptional robustness and protein interactions are associated in yeast.

Bekaert M, Conant GC - BMC Syst Biol (2011)

Bottom Line: Using gene expression data from artificial aneuploid strains of bakers' yeast, we found that genes coding for proteins that physically interact with other proteins show less expression variation in response to aneuploidy than do other genes.This effect is even more pronounced for genes whose products interact with proteins encoded on aneuploid chromosomes.We further found that genes targeted by transcription factors encoded on aneuploid chromosomes were more likely to change in expression after aneuploidy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA. bekaertm@missouri.edu

ABSTRACT

Background: Robustness to insults, both external and internal, is a characteristic feature of life. One level of biological organization for which noise and robustness have been extensively studied is gene expression. Cells have a variety of mechanisms for buffering noise in gene expression, but it is not completely clear what rules govern whether or not a given gene uses such tools to maintain appropriate expression.

Results: Here, we show a general association between the degree to which yeast cells have evolved mechanisms to buffer changes in gene expression and whether they possess protein-protein interactions. We argue that this effect bears an affinity to epistasis, because yeast appears to have evolved regulatory mechanisms such that distant changes in gene copy number for a protein-protein interaction partner gene can alter a gene's expression. This association is not unexpected given recent work linking epistasis and the deleterious effects of changes in gene dosage (i.e., the dosage balance hypothesis). Using gene expression data from artificial aneuploid strains of bakers' yeast, we found that genes coding for proteins that physically interact with other proteins show less expression variation in response to aneuploidy than do other genes. This effect is even more pronounced for genes whose products interact with proteins encoded on aneuploid chromosomes. We further found that genes targeted by transcription factors encoded on aneuploid chromosomes were more likely to change in expression after aneuploidy.

Conclusions: We suggest that these observations can be best understood as resulting from the higher fitness cost of misexpression in epistatic genes and a commensurate greater regulatory control of them.

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Expression variability is increased for genes interacting with the aneuploid chromosome under conditions of rapid cell division. The variability of mRNA expression level (absolute value of fold change) was used as a predictor of the presence of a protein interaction using logistic regression. Three models were tested. The first two predict protein interaction presence (i.e., membership in the set PPI) using the basal mRNA expression variation from either the control (Ctrls, no aneuploid chromosome; solid lines) or the experimental (Expts, presence of an aneuploid chromosome; dashed lines) strains. The third uses expression data to predict the presence of an interaction with a protein encoded on an aneuploid chromosome (i.e., membership in AneuPPI; dotted lines), given that the gene in question is already a member of PPI. (A) Expression measured under rapid growth conditions (batch culture). (B) Expression measured under slow growth conditions (chemostat, phosphate-limited).
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Figure 2: Expression variability is increased for genes interacting with the aneuploid chromosome under conditions of rapid cell division. The variability of mRNA expression level (absolute value of fold change) was used as a predictor of the presence of a protein interaction using logistic regression. Three models were tested. The first two predict protein interaction presence (i.e., membership in the set PPI) using the basal mRNA expression variation from either the control (Ctrls, no aneuploid chromosome; solid lines) or the experimental (Expts, presence of an aneuploid chromosome; dashed lines) strains. The third uses expression data to predict the presence of an interaction with a protein encoded on an aneuploid chromosome (i.e., membership in AneuPPI; dotted lines), given that the gene in question is already a member of PPI. (A) Expression measured under rapid growth conditions (batch culture). (B) Expression measured under slow growth conditions (chemostat, phosphate-limited).

Mentions: The above analyses rest on the introduction of a somewhat arbitrary cutoff for defining genes with post-aneuploidy expression variation. To assess whether this choice might have biased our conclusions, we employed a logistic regression model to evaluate whether measured mRNA variation was predictive of the existence of protein-protein interactions involving a given gene's product. For both the rapid growth batch cultures and the phosphate-limited chemostat ones, mRNA expression variation is an excellent predictor of the presence of an interaction (Figure 2A &2B, respectively). Specifically, we tested three models. For the first two models, we evaluated whether the level of mRNA expression variation predicted the presence of a protein interaction both for the control experiments of Torres et al. [21], where no aneuploid chromosomes were present, and for the aneuploid strains themselves. In both cases, there was a strong negative association between high expression variation and the presence of a protein interaction (P < 10-14 in all cases, Figure 2). Interestingly, this association was reversed when we considered genes with an interaction involving the aneuploid chromosome under fast growing conditions. In that case, we found that mRNA expression variation was positively associated with the presence of such an aneuploid protein interaction (P < 10-11, Figure 2A). We interpret this result as evidence of some regulatory mechanism that tries to balance the expression of genes off the aneuploid chromosome with their interaction partners that are on this chromosome. However it is important to note that, under phosphate-limiting conditions (slow growth), the pattern among the aneuploid interactions was similar to the negative association seen when all interactions were considered (P < 0.003, Figure 2B). We note that our results are robust to the removal of outliers in gene expression variation (points with greater than three-fold variation; data not shown).


Transcriptional robustness and protein interactions are associated in yeast.

Bekaert M, Conant GC - BMC Syst Biol (2011)

Expression variability is increased for genes interacting with the aneuploid chromosome under conditions of rapid cell division. The variability of mRNA expression level (absolute value of fold change) was used as a predictor of the presence of a protein interaction using logistic regression. Three models were tested. The first two predict protein interaction presence (i.e., membership in the set PPI) using the basal mRNA expression variation from either the control (Ctrls, no aneuploid chromosome; solid lines) or the experimental (Expts, presence of an aneuploid chromosome; dashed lines) strains. The third uses expression data to predict the presence of an interaction with a protein encoded on an aneuploid chromosome (i.e., membership in AneuPPI; dotted lines), given that the gene in question is already a member of PPI. (A) Expression measured under rapid growth conditions (batch culture). (B) Expression measured under slow growth conditions (chemostat, phosphate-limited).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3113729&req=5

Figure 2: Expression variability is increased for genes interacting with the aneuploid chromosome under conditions of rapid cell division. The variability of mRNA expression level (absolute value of fold change) was used as a predictor of the presence of a protein interaction using logistic regression. Three models were tested. The first two predict protein interaction presence (i.e., membership in the set PPI) using the basal mRNA expression variation from either the control (Ctrls, no aneuploid chromosome; solid lines) or the experimental (Expts, presence of an aneuploid chromosome; dashed lines) strains. The third uses expression data to predict the presence of an interaction with a protein encoded on an aneuploid chromosome (i.e., membership in AneuPPI; dotted lines), given that the gene in question is already a member of PPI. (A) Expression measured under rapid growth conditions (batch culture). (B) Expression measured under slow growth conditions (chemostat, phosphate-limited).
Mentions: The above analyses rest on the introduction of a somewhat arbitrary cutoff for defining genes with post-aneuploidy expression variation. To assess whether this choice might have biased our conclusions, we employed a logistic regression model to evaluate whether measured mRNA variation was predictive of the existence of protein-protein interactions involving a given gene's product. For both the rapid growth batch cultures and the phosphate-limited chemostat ones, mRNA expression variation is an excellent predictor of the presence of an interaction (Figure 2A &2B, respectively). Specifically, we tested three models. For the first two models, we evaluated whether the level of mRNA expression variation predicted the presence of a protein interaction both for the control experiments of Torres et al. [21], where no aneuploid chromosomes were present, and for the aneuploid strains themselves. In both cases, there was a strong negative association between high expression variation and the presence of a protein interaction (P < 10-14 in all cases, Figure 2). Interestingly, this association was reversed when we considered genes with an interaction involving the aneuploid chromosome under fast growing conditions. In that case, we found that mRNA expression variation was positively associated with the presence of such an aneuploid protein interaction (P < 10-11, Figure 2A). We interpret this result as evidence of some regulatory mechanism that tries to balance the expression of genes off the aneuploid chromosome with their interaction partners that are on this chromosome. However it is important to note that, under phosphate-limiting conditions (slow growth), the pattern among the aneuploid interactions was similar to the negative association seen when all interactions were considered (P < 0.003, Figure 2B). We note that our results are robust to the removal of outliers in gene expression variation (points with greater than three-fold variation; data not shown).

Bottom Line: Using gene expression data from artificial aneuploid strains of bakers' yeast, we found that genes coding for proteins that physically interact with other proteins show less expression variation in response to aneuploidy than do other genes.This effect is even more pronounced for genes whose products interact with proteins encoded on aneuploid chromosomes.We further found that genes targeted by transcription factors encoded on aneuploid chromosomes were more likely to change in expression after aneuploidy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Animal Sciences, University of Missouri, Columbia, MO 65211, USA. bekaertm@missouri.edu

ABSTRACT

Background: Robustness to insults, both external and internal, is a characteristic feature of life. One level of biological organization for which noise and robustness have been extensively studied is gene expression. Cells have a variety of mechanisms for buffering noise in gene expression, but it is not completely clear what rules govern whether or not a given gene uses such tools to maintain appropriate expression.

Results: Here, we show a general association between the degree to which yeast cells have evolved mechanisms to buffer changes in gene expression and whether they possess protein-protein interactions. We argue that this effect bears an affinity to epistasis, because yeast appears to have evolved regulatory mechanisms such that distant changes in gene copy number for a protein-protein interaction partner gene can alter a gene's expression. This association is not unexpected given recent work linking epistasis and the deleterious effects of changes in gene dosage (i.e., the dosage balance hypothesis). Using gene expression data from artificial aneuploid strains of bakers' yeast, we found that genes coding for proteins that physically interact with other proteins show less expression variation in response to aneuploidy than do other genes. This effect is even more pronounced for genes whose products interact with proteins encoded on aneuploid chromosomes. We further found that genes targeted by transcription factors encoded on aneuploid chromosomes were more likely to change in expression after aneuploidy.

Conclusions: We suggest that these observations can be best understood as resulting from the higher fitness cost of misexpression in epistatic genes and a commensurate greater regulatory control of them.

Show MeSH
Related in: MedlinePlus