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:

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.

Supplementary Files:

Attachment	Size
Supplementary Excel Files for Rustad et al. 2014	19.36 MB
TFOE Searchable Excel File	20.15 MB

Title	Gene	BioProject	GEO Series	Platform	Accession	Sample Method	Sample Type	References	Release Date	Repository
TFOE_9607_0020c_C	Rv0020c	PRJNA254351	GSE59086	GPL14824	GSM1426370	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_1636_0022c_C	Rv0022c WhiB family transcriptional regulator	PRJNA254351	GSE59086	GPL14824	GSM1426371	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_6389_0022c_B	Rv0022c WhiB family transcriptional regulator	PRJNA254351	GSE59086	GPL14824	GSM1426372	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_7607_0022c	Rv0022c WhiB family transcriptional regulator	PRJNA254351	GSE59086	GPL14824	GSM1426373	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_4883_0023	Rv0023 Transcriptional regulatory protein	PRJNA254351	GSE59086	GPL14824	GSM1426374	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_8686_0023_C	Rv0023 Transcriptional regulatory protein	PRJNA254351	GSE59086	GPL14824	GSM1426375	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_4399_0117_C	Rv0117 Hydrogen peroxide-inducible genes activator	PRJNA254351	GSE59086	GPL14824	GSM1426408	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_2431_0054	Rv0054 Single-stranded DNA-binding protein	PRJNA254351	GSE59086	GPL14824	GSM1426390	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_7211_0081_2B	Rv0081 transcriptional regulator, ArsR family	PRJNA254351	GSE59086	GPL14824	GSM1426404	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_8710_0081	Rv0081 transcriptional regulator, ArsR family	PRJNA254351	GSE59086	GPL14824	GSM1426405	Tiling Array	RNA	25232098	4-Jul-14	GEO