Mapping and manipulating the Mycobacterium tuberculosis transcriptome using a transcription factor overexpression-derived regulatory network.

Publication Type:

Journal Article

Authors:

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

Source:

Genome Biol, Volume 15, Issue 11, p.502 (2014)

Keywords:

Cloning, Molecular, Gene Expression Regulation, Bacterial, Gene Regulatory Networks, Humans, Isoniazid, Mycobacterium tuberculosis, Promoter Regions, Genetic, Regulon, Transcription Factors, Transcription, Genetic, Transcriptome, Tuberculosis

Abstract:

<p><b>BACKGROUND: </b>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.</p><p><b>RESULTS: </b>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.</p><p><b>CONCLUSION: </b>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.</p>

Supplementary Files: 
AttachmentSize
File Supplementary Excel Files for Rustad et al. 201419.36 MB
File TFOE Searchable Excel File20.15 MB

TFOE Expression Data Records

Title Gene BioProject GEO Series Platform Accession Sample Method Sample Type References Release Date Repository
TFOE_1581_0894
Rv0894
Disease resistance domain-containing protein
 PRJNA254351 GSE59086 GPL14824 GSM1426587 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_4073_0894
Rv0894
Disease resistance domain-containing protein
 PRJNA254351 GSE59086 GPL14824 GSM1426588 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_5872_0894
Rv0894
Disease resistance domain-containing protein
 PRJNA254351 GSE59086 GPL14824 GSM1426589 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_6292_0844c
Rv0844c
DNA-binding response regulator, LuxR family
 PRJNA254351 GSE59086 GPL14824 GSM1426578 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_9932_0827c
Rv0827c
transcriptional regulator, ArsR family
 PRJNA254351 GSE59086 GPL14824 GSM1426577 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_9505_0827c
Rv0827c
transcriptional regulator, ArsR family
 PRJNA254351 GSE59086 GPL14824 GSM1426576 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_6079_0818
Rv0818
Phosphate regulon transcriptional regulatory protein PhoB (SphR)
 PRJNA254351 GSE59086 GPL14824 GSM1426566 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_4668_0821c
Rv0821c
Phosphate transport system regulatory protein PhoU
 PRJNA254351 GSE59086 GPL14824 GSM1426567 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_5436_0821c
Rv0821c
Phosphate transport system regulatory protein PhoU
 PRJNA254351 GSE59086 GPL14824 GSM1426568 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_9343_0821c
Rv0821c
Phosphate transport system regulatory protein PhoU
 PRJNA254351 GSE59086 GPL14824 GSM1426569 Tiling Array RNA 25232098 4-Jul-14 GEO