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Regulatory network structure as a dominant determinant of transcription factor evolutionary rate.

Coulombe-Huntington J, Xia Y - PLoS Comput. Biol. (2012)

Bottom Line: We found significantly distinct trends relating TF evolutionary rate to mRNA expression level, codon adaptation index, the evolutionary rate of physical interaction partners, and, confirming previous reports, to protein-protein interaction degree and regulatory in-degree.Finally, we discuss likely causes for TFs' different evolutionary relationship to the physical interaction network, such as the prevalence of transient interactions in the TF subnetwork.This work suggests that positive and negative regulatory networks follow very different evolutionary rules, and that transcription factor evolution is best understood at a network- or systems-level.

View Article: PubMed Central - PubMed

Affiliation: Bioinformatics Program, Boston University, Boston, MA, USA. jasmin@bu.edu

ABSTRACT
The evolution of transcriptional regulatory networks has thus far mostly been studied at the level of cis-regulatory elements. To gain a complete understanding of regulatory network evolution we must also study the evolutionary role of trans-factors, such as transcription factors (TFs). Here, we systematically assess genomic and network-level determinants of TF evolutionary rate in yeast, and how they compare to those of generic proteins, while carefully controlling for differences of the TF protein set, such as expression level. We found significantly distinct trends relating TF evolutionary rate to mRNA expression level, codon adaptation index, the evolutionary rate of physical interaction partners, and, confirming previous reports, to protein-protein interaction degree and regulatory in-degree. We discovered that for TFs, the dominant determinants of evolutionary rate lie in the structure of the regulatory network, such as the median evolutionary rate of target genes and the fraction of species-specific target genes. Decomposing the regulatory network by edge sign, we found that this modular evolution of TFs and their targets is limited to activating regulatory relationships. We show that fast evolving TFs tend to regulate other TFs and niche-specific processes and that their targets show larger evolutionary expression changes than targets of other TFs. We also show that the positive trend relating TF regulatory in-degree and evolutionary rate is likely related to the species-specificity of the transcriptional regulation modules. Finally, we discuss likely causes for TFs' different evolutionary relationship to the physical interaction network, such as the prevalence of transient interactions in the TF subnetwork. This work suggests that positive and negative regulatory networks follow very different evolutionary rules, and that transcription factor evolution is best understood at a network- or systems-level.

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Targets of fast evolving TFs have larger expression changes through evolution.The targets of the 25% fastest evolving TFs, on the right, have on average larger absolute fold changes in expression between S. cerevisiae and S. paradoxus than targets of other TFs, on the left, as determined by RNA-seq. Numbers above the bars represent the number of TFs in the bin.
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pcbi-1002734-g004: Targets of fast evolving TFs have larger expression changes through evolution.The targets of the 25% fastest evolving TFs, on the right, have on average larger absolute fold changes in expression between S. cerevisiae and S. paradoxus than targets of other TFs, on the left, as determined by RNA-seq. Numbers above the bars represent the number of TFs in the bin.

Mentions: The role of trans-regulatory gene evolution on gene expression is inherently more difficult to study than cis-regulatory evolution since the former requires knowledge of the regulatory network structure. To confirm that the evolutionary rate of TFs is related to measurable trans-regulatory changes in the gene expression of target genes, we used previously published RNA-seq data from both S. cerevisiae and S. paradoxus[21]. Using the network of confirmed ChIP-chip edges, we found that targets of the top 25% fastest evolving TFs had, on average, larger expression differences between the two species than targets of other TFs, as shown in Figure 4 (t-test pā€Š=ā€Š0.00013, see Methods for details). This result confirms that TF evolutionary rate can serve to predict real trans-regulatory expression changes of gene modules, which could in turn lead to important phenotypic effects.


Regulatory network structure as a dominant determinant of transcription factor evolutionary rate.

Coulombe-Huntington J, Xia Y - PLoS Comput. Biol. (2012)

Targets of fast evolving TFs have larger expression changes through evolution.The targets of the 25% fastest evolving TFs, on the right, have on average larger absolute fold changes in expression between S. cerevisiae and S. paradoxus than targets of other TFs, on the left, as determined by RNA-seq. Numbers above the bars represent the number of TFs in the bin.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475661&req=5

pcbi-1002734-g004: Targets of fast evolving TFs have larger expression changes through evolution.The targets of the 25% fastest evolving TFs, on the right, have on average larger absolute fold changes in expression between S. cerevisiae and S. paradoxus than targets of other TFs, on the left, as determined by RNA-seq. Numbers above the bars represent the number of TFs in the bin.
Mentions: The role of trans-regulatory gene evolution on gene expression is inherently more difficult to study than cis-regulatory evolution since the former requires knowledge of the regulatory network structure. To confirm that the evolutionary rate of TFs is related to measurable trans-regulatory changes in the gene expression of target genes, we used previously published RNA-seq data from both S. cerevisiae and S. paradoxus[21]. Using the network of confirmed ChIP-chip edges, we found that targets of the top 25% fastest evolving TFs had, on average, larger expression differences between the two species than targets of other TFs, as shown in Figure 4 (t-test pā€Š=ā€Š0.00013, see Methods for details). This result confirms that TF evolutionary rate can serve to predict real trans-regulatory expression changes of gene modules, which could in turn lead to important phenotypic effects.

Bottom Line: We found significantly distinct trends relating TF evolutionary rate to mRNA expression level, codon adaptation index, the evolutionary rate of physical interaction partners, and, confirming previous reports, to protein-protein interaction degree and regulatory in-degree.Finally, we discuss likely causes for TFs' different evolutionary relationship to the physical interaction network, such as the prevalence of transient interactions in the TF subnetwork.This work suggests that positive and negative regulatory networks follow very different evolutionary rules, and that transcription factor evolution is best understood at a network- or systems-level.

View Article: PubMed Central - PubMed

Affiliation: Bioinformatics Program, Boston University, Boston, MA, USA. jasmin@bu.edu

ABSTRACT
The evolution of transcriptional regulatory networks has thus far mostly been studied at the level of cis-regulatory elements. To gain a complete understanding of regulatory network evolution we must also study the evolutionary role of trans-factors, such as transcription factors (TFs). Here, we systematically assess genomic and network-level determinants of TF evolutionary rate in yeast, and how they compare to those of generic proteins, while carefully controlling for differences of the TF protein set, such as expression level. We found significantly distinct trends relating TF evolutionary rate to mRNA expression level, codon adaptation index, the evolutionary rate of physical interaction partners, and, confirming previous reports, to protein-protein interaction degree and regulatory in-degree. We discovered that for TFs, the dominant determinants of evolutionary rate lie in the structure of the regulatory network, such as the median evolutionary rate of target genes and the fraction of species-specific target genes. Decomposing the regulatory network by edge sign, we found that this modular evolution of TFs and their targets is limited to activating regulatory relationships. We show that fast evolving TFs tend to regulate other TFs and niche-specific processes and that their targets show larger evolutionary expression changes than targets of other TFs. We also show that the positive trend relating TF regulatory in-degree and evolutionary rate is likely related to the species-specificity of the transcriptional regulation modules. Finally, we discuss likely causes for TFs' different evolutionary relationship to the physical interaction network, such as the prevalence of transient interactions in the TF subnetwork. This work suggests that positive and negative regulatory networks follow very different evolutionary rules, and that transcription factor evolution is best understood at a network- or systems-level.

Show MeSH