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_6605_0608	Rv0608	PRJNA254351	GSE59086	GPL14824	GSM1426519	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_7909_0608	Rv0608	PRJNA254351	GSE59086	GPL14824	GSM1426520	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_4083_0623	Rv0623	PRJNA254351	GSE59086	GPL14824	GSM1426521	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_5155_0623	Rv0623	PRJNA254351	GSE59086	GPL14824	GSM1426522	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_5381_0623	Rv0623	PRJNA254351	GSE59086	GPL14824	GSM1426523	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_2192_0653c_B	Rv0653c Transcriptional regulator, TetR family	PRJNA254351	GSE59086	GPL14824	GSM1426524	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_8204_0681	Rv0681 Transcriptional regulator, TetR family	PRJNA254351	GSE59086	GPL14824	GSM1426539	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_4612_0792c	Rv0792c PF00070 family, FAD-dependent NAD(P)-disulphide oxidoreductase	PRJNA254351	GSE59086	GPL14824	GSM1426560	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_1634_0757	Rv0757 DNA-binding response regulator	PRJNA254351	GSE59086	GPL14824	GSM1426553	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_2546_0757	Rv0757 DNA-binding response regulator	PRJNA254351	GSE59086	GPL14824	GSM1426554	Tiling Array	RNA	25232098	4-Jul-14	GEO