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_2838_0494_C
Rv0494
Lactate-responsive regulator LldR in Enterobacteria, GntR family
 PRJNA254351 GSE59086 GPL14824 GSM1426503 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_2101_0494_B
Rv0494
Lactate-responsive regulator LldR in Enterobacteria, GntR family
 PRJNA254351 GSE59086 GPL14824 GSM1426502 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_1632_0474_C
Rv0474
\Transcriptional regulator, XRE family\\\""
 PRJNA254351 GSE59086 GPL14824 GSM1426492 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_6945_0474_A
Rv0474
\Transcriptional regulator, XRE family\\\""
 PRJNA254351 GSE59086 GPL14824 GSM1426493 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_9656_0474_B
Rv0474
\Transcriptional regulator, XRE family\\\""
 PRJNA254351 GSE59086 GPL14824 GSM1426494 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_1488_0485
Rv0485
Transcriptional regulatory protein
 PRJNA254351 GSE59086 GPL14824 GSM1426495 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_1660_0485_B
Rv0485
Transcriptional regulatory protein
 PRJNA254351 GSE59086 GPL14824 GSM1426496 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_1557_0474_B
Rv0474
\Transcriptional regulator, XRE family\\\""
 PRJNA254351 GSE59086 GPL14824 GSM1426491 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_2722_0491
Rv0491
Phosphate regulon transcriptional regulatory protein PhoB (SphR); Sensory transduction protein regX3
 PRJNA254351 GSE59086 GPL14824 GSM1426498 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_7387_0491_B
Rv0491
Phosphate regulon transcriptional regulatory protein PhoB (SphR); Sensory transduction protein regX3
 PRJNA254351 GSE59086 GPL14824 GSM1426499 Tiling Array RNA 25232098 4-Jul-14 GEO