Inferring condition-specific modulation of transcription factor activity in yeast through regulon-based analysis of genomewide expression.
A key goal of systems biology is to understand how genomewide mRNA expression levels are controlled by transcription factors (TFs) in a condition-specific fashion. TF activity is frequently modulated at the post-translational level through ligand binding, covalent modification, or changes in sub-cel...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2008-09-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2518834?pdf=render |
| _version_ | 1811276563348455424 |
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| author | André Boorsma Xiang-Jun Lu Anna Zakrzewska Frans M Klis Harmen J Bussemaker |
| author_facet | André Boorsma Xiang-Jun Lu Anna Zakrzewska Frans M Klis Harmen J Bussemaker |
| author_sort | André Boorsma |
| collection | DOAJ |
| description | A key goal of systems biology is to understand how genomewide mRNA expression levels are controlled by transcription factors (TFs) in a condition-specific fashion. TF activity is frequently modulated at the post-translational level through ligand binding, covalent modification, or changes in sub-cellular localization. In this paper, we demonstrate how prior information about regulatory network connectivity can be exploited to infer condition-specific TF activity as a hidden variable from the genomewide mRNA expression pattern in the yeast Saccharomyces cerevisiae.We first validate experimentally that by scoring differential expression at the level of gene sets or "regulons" comprised of the putative targets of a TF, we can accurately predict modulation of TF activity at the post-translational level. Next, we create an interactive database of inferred activities for a large number of TFs across a large number of experimental conditions in S. cerevisiae. This allows us to perform TF-centric analysis of the yeast regulatory network.We analyze the degree to which the mRNA expression level of each TF is predictive of its regulatory activity. We also organize TFs into "co-modulation networks" based on their inferred activity profile across conditions, and find that this reveals functional and mechanistic relationships. Finally, we present evidence that the PAC and rRPE motifs antagonize TBP-dependent regulation, and function as core promoter elements governed by the transcription regulator NC2. Regulon-based monitoring of TF activity modulation is a powerful tool for analyzing regulatory network function that should be applicable in other organisms. Tools and results are available online at http://bussemakerlab.org/RegulonProfiler/. |
| first_indexed | 2024-04-12T23:59:55Z |
| format | Article |
| id | doaj.art-1ffedef2ec9e4ea7ae15113e34364bbb |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T23:59:55Z |
| publishDate | 2008-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-1ffedef2ec9e4ea7ae15113e34364bbb2022-12-22T03:11:23ZengPublic Library of Science (PLoS)PLoS ONE1932-62032008-09-0139e311210.1371/journal.pone.0003112Inferring condition-specific modulation of transcription factor activity in yeast through regulon-based analysis of genomewide expression.André BoorsmaXiang-Jun LuAnna ZakrzewskaFrans M KlisHarmen J BussemakerA key goal of systems biology is to understand how genomewide mRNA expression levels are controlled by transcription factors (TFs) in a condition-specific fashion. TF activity is frequently modulated at the post-translational level through ligand binding, covalent modification, or changes in sub-cellular localization. In this paper, we demonstrate how prior information about regulatory network connectivity can be exploited to infer condition-specific TF activity as a hidden variable from the genomewide mRNA expression pattern in the yeast Saccharomyces cerevisiae.We first validate experimentally that by scoring differential expression at the level of gene sets or "regulons" comprised of the putative targets of a TF, we can accurately predict modulation of TF activity at the post-translational level. Next, we create an interactive database of inferred activities for a large number of TFs across a large number of experimental conditions in S. cerevisiae. This allows us to perform TF-centric analysis of the yeast regulatory network.We analyze the degree to which the mRNA expression level of each TF is predictive of its regulatory activity. We also organize TFs into "co-modulation networks" based on their inferred activity profile across conditions, and find that this reveals functional and mechanistic relationships. Finally, we present evidence that the PAC and rRPE motifs antagonize TBP-dependent regulation, and function as core promoter elements governed by the transcription regulator NC2. Regulon-based monitoring of TF activity modulation is a powerful tool for analyzing regulatory network function that should be applicable in other organisms. Tools and results are available online at http://bussemakerlab.org/RegulonProfiler/.http://europepmc.org/articles/PMC2518834?pdf=render |
| spellingShingle | André Boorsma Xiang-Jun Lu Anna Zakrzewska Frans M Klis Harmen J Bussemaker Inferring condition-specific modulation of transcription factor activity in yeast through regulon-based analysis of genomewide expression. PLoS ONE |
| title | Inferring condition-specific modulation of transcription factor activity in yeast through regulon-based analysis of genomewide expression. |
| title_full | Inferring condition-specific modulation of transcription factor activity in yeast through regulon-based analysis of genomewide expression. |
| title_fullStr | Inferring condition-specific modulation of transcription factor activity in yeast through regulon-based analysis of genomewide expression. |
| title_full_unstemmed | Inferring condition-specific modulation of transcription factor activity in yeast through regulon-based analysis of genomewide expression. |
| title_short | Inferring condition-specific modulation of transcription factor activity in yeast through regulon-based analysis of genomewide expression. |
| title_sort | inferring condition specific modulation of transcription factor activity in yeast through regulon based analysis of genomewide expression |
| url | http://europepmc.org/articles/PMC2518834?pdf=render |
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