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_7750_3597c
Rv3597c
Histone protein Lsr2
 PRJNA254351 GSE59086 GPL14824 GSM1427019 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_3847_3676
Rv3676
cAMP-binding proteins - catabolite gene activator and regulatory subunit of cAMP-dependent protein kinases
 PRJNA254351 GSE59086 GPL14824 GSM1427020 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_4445_3676
Rv3676
cAMP-binding proteins - catabolite gene activator and regulatory subunit of cAMP-dependent protein kinases
 PRJNA254351 GSE59086 GPL14824 GSM1427021 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_6346_3676
Rv3676
cAMP-binding proteins - catabolite gene activator and regulatory subunit of cAMP-dependent protein kinases
 PRJNA254351 GSE59086 GPL14824 GSM1427022 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_9192_3681c
Rv3681c
WhiB-type transcription regulator
 PRJNA254351 GSE59086 GPL14824 GSM1427024 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_9798_3681c
Rv3681c
WhiB-type transcription regulator
 PRJNA254351 GSE59086 GPL14824 GSM1427025 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_1864_3830c
Rv3830c
Beta-carotene ketolase (EC 1.14.-.-)
 PRJNA254351 GSE59086 GPL14824 GSM1427038 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_8264_3830c
Rv3830c
Beta-carotene ketolase (EC 1.14.-.-)
 PRJNA254351 GSE59086 GPL14824 GSM1427039 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_9939_3830c
Rv3830c
Beta-carotene ketolase (EC 1.14.-.-)
 PRJNA254351 GSE59086 GPL14824 GSM1427040 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_3194_3855
Rv3855
Transcriptional repressor EthR, TetR family
 PRJNA254351 GSE59086 GPL14824 GSM1427054 Tiling Array RNA 25232098 4-Jul-14 GEO