Cargando…
Mapping and manipulating the Mycobacterium tuberculosis transcriptome using a transcription factor overexpression-derived regulatory network
BACKGROUND: Mycobacterium tuberculosis senses and responds to the shifting and hostile landscape of the host. To characterize the underlying intertwined gene regulatory network governed by approximately 200 transcription factors of M. tuberculosis, we have assayed the global transcriptional conseque...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4249609/ https://www.ncbi.nlm.nih.gov/pubmed/25380655 http://dx.doi.org/10.1186/s13059-014-0502-3 |
_version_ | 1782346867424624640 |
---|---|
author | Rustad, Tige R Minch, Kyle J Ma, Shuyi Winkler, Jessica K Hobbs, Samuel Hickey, Mark Brabant, William Turkarslan, Serdar Price, Nathan D Baliga, Nitin S Sherman, David R |
author_facet | Rustad, Tige R Minch, Kyle J Ma, Shuyi Winkler, Jessica K Hobbs, Samuel Hickey, Mark Brabant, William Turkarslan, Serdar Price, Nathan D Baliga, Nitin S Sherman, David R |
author_sort | Rustad, Tige R |
collection | PubMed |
description | BACKGROUND: Mycobacterium tuberculosis senses and responds to the shifting and hostile landscape of the host. To characterize the underlying intertwined gene regulatory network governed by approximately 200 transcription factors of M. tuberculosis, we have assayed the global transcriptional consequences of overexpressing each transcription factor from an inducible promoter. RESULTS: We cloned and overexpressed 206 transcription factors in M. tuberculosis to identify the regulatory signature of each. We identified 9,335 regulatory consequences of overexpressing each of 183 transcription factors, providing evidence of regulation for 70% of the M. tuberculosis genome. These transcriptional signatures agree well with previously described M. tuberculosis regulons. The number of genes differentially regulated by transcription factor overexpression varied from hundreds of genes to none, with the majority of expression changes repressing basal transcription. Exploring the global transcriptional maps of transcription factor overexpressing (TFOE) strains, we predicted and validated the phenotype of a regulator that reduces susceptibility to a first line anti-tubercular drug, isoniazid. We also combined the TFOE data with an existing model of M. tuberculosis metabolism to predict the growth rates of individual TFOE strains with high fidelity. CONCLUSION: This work has led to a systems-level framework describing the transcriptome of a devastating bacterial pathogen, characterized the transcriptional influence of nearly all individual transcription factors in M. tuberculosis, and demonstrated the utility of this resource. These results will stimulate additional systems-level and hypothesis-driven efforts to understand M. tuberculosis adaptations that promote disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-014-0502-3) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4249609 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-42496092014-12-02 Mapping and manipulating the Mycobacterium tuberculosis transcriptome using a transcription factor overexpression-derived regulatory network Rustad, Tige R Minch, Kyle J Ma, Shuyi Winkler, Jessica K Hobbs, Samuel Hickey, Mark Brabant, William Turkarslan, Serdar Price, Nathan D Baliga, Nitin S Sherman, David R Genome Biol Research BACKGROUND: Mycobacterium tuberculosis senses and responds to the shifting and hostile landscape of the host. To characterize the underlying intertwined gene regulatory network governed by approximately 200 transcription factors of M. tuberculosis, we have assayed the global transcriptional consequences of overexpressing each transcription factor from an inducible promoter. RESULTS: We cloned and overexpressed 206 transcription factors in M. tuberculosis to identify the regulatory signature of each. We identified 9,335 regulatory consequences of overexpressing each of 183 transcription factors, providing evidence of regulation for 70% of the M. tuberculosis genome. These transcriptional signatures agree well with previously described M. tuberculosis regulons. The number of genes differentially regulated by transcription factor overexpression varied from hundreds of genes to none, with the majority of expression changes repressing basal transcription. Exploring the global transcriptional maps of transcription factor overexpressing (TFOE) strains, we predicted and validated the phenotype of a regulator that reduces susceptibility to a first line anti-tubercular drug, isoniazid. We also combined the TFOE data with an existing model of M. tuberculosis metabolism to predict the growth rates of individual TFOE strains with high fidelity. CONCLUSION: This work has led to a systems-level framework describing the transcriptome of a devastating bacterial pathogen, characterized the transcriptional influence of nearly all individual transcription factors in M. tuberculosis, and demonstrated the utility of this resource. These results will stimulate additional systems-level and hypothesis-driven efforts to understand M. tuberculosis adaptations that promote disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-014-0502-3) contains supplementary material, which is available to authorized users. BioMed Central 2014-11-03 2014 /pmc/articles/PMC4249609/ /pubmed/25380655 http://dx.doi.org/10.1186/s13059-014-0502-3 Text en © Rustad et al.; licensee BioMed Central Ltd. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Rustad, Tige R Minch, Kyle J Ma, Shuyi Winkler, Jessica K Hobbs, Samuel Hickey, Mark Brabant, William Turkarslan, Serdar Price, Nathan D Baliga, Nitin S Sherman, David R Mapping and manipulating the Mycobacterium tuberculosis transcriptome using a transcription factor overexpression-derived regulatory network |
title | Mapping and manipulating the Mycobacterium tuberculosis transcriptome using a transcription factor overexpression-derived regulatory network |
title_full | Mapping and manipulating the Mycobacterium tuberculosis transcriptome using a transcription factor overexpression-derived regulatory network |
title_fullStr | Mapping and manipulating the Mycobacterium tuberculosis transcriptome using a transcription factor overexpression-derived regulatory network |
title_full_unstemmed | Mapping and manipulating the Mycobacterium tuberculosis transcriptome using a transcription factor overexpression-derived regulatory network |
title_short | Mapping and manipulating the Mycobacterium tuberculosis transcriptome using a transcription factor overexpression-derived regulatory network |
title_sort | mapping and manipulating the mycobacterium tuberculosis transcriptome using a transcription factor overexpression-derived regulatory network |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4249609/ https://www.ncbi.nlm.nih.gov/pubmed/25380655 http://dx.doi.org/10.1186/s13059-014-0502-3 |
work_keys_str_mv | AT rustadtiger mappingandmanipulatingthemycobacteriumtuberculosistranscriptomeusingatranscriptionfactoroverexpressionderivedregulatorynetwork AT minchkylej mappingandmanipulatingthemycobacteriumtuberculosistranscriptomeusingatranscriptionfactoroverexpressionderivedregulatorynetwork AT mashuyi mappingandmanipulatingthemycobacteriumtuberculosistranscriptomeusingatranscriptionfactoroverexpressionderivedregulatorynetwork AT winklerjessicak mappingandmanipulatingthemycobacteriumtuberculosistranscriptomeusingatranscriptionfactoroverexpressionderivedregulatorynetwork AT hobbssamuel mappingandmanipulatingthemycobacteriumtuberculosistranscriptomeusingatranscriptionfactoroverexpressionderivedregulatorynetwork AT hickeymark mappingandmanipulatingthemycobacteriumtuberculosistranscriptomeusingatranscriptionfactoroverexpressionderivedregulatorynetwork AT brabantwilliam mappingandmanipulatingthemycobacteriumtuberculosistranscriptomeusingatranscriptionfactoroverexpressionderivedregulatorynetwork AT turkarslanserdar mappingandmanipulatingthemycobacteriumtuberculosistranscriptomeusingatranscriptionfactoroverexpressionderivedregulatorynetwork AT pricenathand mappingandmanipulatingthemycobacteriumtuberculosistranscriptomeusingatranscriptionfactoroverexpressionderivedregulatorynetwork AT baliganitins mappingandmanipulatingthemycobacteriumtuberculosistranscriptomeusingatranscriptionfactoroverexpressionderivedregulatorynetwork AT shermandavidr mappingandmanipulatingthemycobacteriumtuberculosistranscriptomeusingatranscriptionfactoroverexpressionderivedregulatorynetwork |