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_6335_0576_B	Rv0576 Transcriptional regulator, ArsR family	PRJNA254351	GSE59086	GPL14824	GSM1426507	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_7778_0576_C	Rv0576 Transcriptional regulator, ArsR family	PRJNA254351	GSE59086	GPL14824	GSM1426508	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_3199_0586_C	Rv0586 Transcriptional regulator, GntR family	PRJNA254351	GSE59086	GPL14824	GSM1426509	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_4503_0586_B	Rv0586 Transcriptional regulator, GntR family	PRJNA254351	GSE59086	GPL14824	GSM1426510	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_6778_0586	Rv0586 Transcriptional regulator, GntR family	PRJNA254351	GSE59086	GPL14824	GSM1426511	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_3450_0599c	Rv0599c	PRJNA254351	GSE59086	GPL14824	GSM1426512	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_4634_0599c	Rv0599c	PRJNA254351	GSE59086	GPL14824	GSM1426513	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_5228_0599c	Rv0599c	PRJNA254351	GSE59086	GPL14824	GSM1426514	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_5597_0485_C	Rv0485 Transcriptional regulatory protein	PRJNA254351	GSE59086	GPL14824	GSM1426497	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_9438_0494_B	Rv0494 Lactate-responsive regulator LldR in Enterobacteria, GntR family	PRJNA254351	GSE59086	GPL14824	GSM1426504	Tiling Array	RNA	25232098	4-Jul-14	GEO