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

Publication Type:

Journal Article

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: 

TFOE Expression Data Records

Title Gene BioProject GEO Series Platform Accession Sample Method Sample Type References Release Date Repository
TFOE_2777_0757
DNA-binding response regulator
PRJNA254351 GSE59086 GPL14824 GSM1426555 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_2591_0767c
Transcriptional regulator, TetR family
PRJNA254351 GSE59086 GPL14824 GSM1426556 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_4251_0767c
Transcriptional regulator, TetR family
PRJNA254351 GSE59086 GPL14824 GSM1426557 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_8010_0767c
Transcriptional regulator, TetR family
PRJNA254351 GSE59086 GPL14824 GSM1426558 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_3681_0792c
PF00070 family, FAD-dependent NAD(P)-disulphide oxidoreductase
PRJNA254351 GSE59086 GPL14824 GSM1426559 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_4698_0818
Phosphate regulon transcriptional regulatory protein PhoB (SphR)
PRJNA254351 GSE59086 GPL14824 GSM1426564 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_6352_0792c
PF00070 family, FAD-dependent NAD(P)-disulphide oxidoreductase
PRJNA254351 GSE59086 GPL14824 GSM1426561 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_6585_0792c
PF00070 family, FAD-dependent NAD(P)-disulphide oxidoreductase
PRJNA254351 GSE59086 GPL14824 GSM1426562 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_8354_0792c_C
PF00070 family, FAD-dependent NAD(P)-disulphide oxidoreductase
PRJNA254351 GSE59086 GPL14824 GSM1426563 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_1255_0757_b
DNA-binding response regulator
PRJNA254351 GSE59086 GPL14824 GSM1426552 Tiling Array RNA 25232098 4-Jul-14 GEO