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_8453_1963c	Rv1963c Transcriptional repressor Mce3R, TetR family	PRJNA254351	GSE59086	GPL14824	GSM1426756	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_2686_1985b2		PRJNA254351	GSE59086	GPL14824	GSM1426757	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_5735_1985c	Rv1985c HTH-type transcriptional regulator	PRJNA254351	GSE59086	GPL14824	GSM1426758	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_7345_1985c_B	Rv1985c HTH-type transcriptional regulator	PRJNA254351	GSE59086	GPL14824	GSM1426759	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_7976_1985_a2		PRJNA254351	GSE59086	GPL14824	GSM1426760	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_8072_1985c_A	Rv1985c HTH-type transcriptional regulator	PRJNA254351	GSE59086	GPL14824	GSM1426761	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_9172_1985c	Rv1985c HTH-type transcriptional regulator	PRJNA254351	GSE59086	GPL14824	GSM1426762	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_1201_1990c_a	Rv1990c	PRJNA254351	GSE59086	GPL14824	GSM1426763	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_9027_1960c	Rv1960c Antitoxin ParD1	PRJNA254351	GSE59086	GPL14824	GSM1426753	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_3220_1960c	Rv1960c Antitoxin ParD1	PRJNA254351	GSE59086	GPL14824	GSM1426752	Tiling Array	RNA	25232098	4-Jul-14	GEO