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_8192_3849	Rv3849 ESX-1 secreted protein regulator EspR	PRJNA254351	GSE59086	GPL14824	GSM1427049	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_2894_3852	Rv3852 POSSIBLE HISTONE-LIKE PROTEIN HNS	PRJNA254351	GSE59086	GPL14824	GSM1427050	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_1113_3328c	Rv3328c putative RNA polymerase sigma factor	PRJNA254351	GSE59086	GPL14824	GSM1426982	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_9162_3301c	Rv3301c Phosphate transport system regulatory protein PhoU	PRJNA254351	GSE59086	GPL14824	GSM1426981	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_4398_3301c	Rv3301c Phosphate transport system regulatory protein PhoU	PRJNA254351	GSE59086	GPL14824	GSM1426979	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_9882_3295_C	Rv3295 Transcriptional regulator, TetR family	PRJNA254351	GSE59086	GPL14824	GSM1426978	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_2203_3328c	Rv3328c putative RNA polymerase sigma factor	PRJNA254351	GSE59086	GPL14824	GSM1426983	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_4667_3328c	Rv3328c putative RNA polymerase sigma factor	PRJNA254351	GSE59086	GPL14824	GSM1426984	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_3290_3334	Rv3334 Mercuric resistance operon regulatory protein	PRJNA254351	GSE59086	GPL14824	GSM1426985	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_3349_3334	Rv3334 Mercuric resistance operon regulatory protein	PRJNA254351	GSE59086	GPL14824	GSM1426986	Tiling Array	RNA	25232098	4-Jul-14	GEO