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_2815_1287	Rv1287 Predicted transcriptional regulator of sulfate adenylyltransferase, Rrf2 family	PRJNA254351	GSE59086	GPL14824	GSM1426652	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_5462_1221	Rv1221 RNA polymerase sigma-70 factor, ECF subfamily	PRJNA254351	GSE59086	GPL14824	GSM1426641	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_6677_1221	Rv1221 RNA polymerase sigma-70 factor, ECF subfamily	PRJNA254351	GSE59086	GPL14824	GSM1426642	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_3722_1255c	Rv1255c Possible oxidoreductase subunit	PRJNA254351	GSE59086	GPL14824	GSM1426643	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_4094_1255c	Rv1255c Possible oxidoreductase subunit	PRJNA254351	GSE59086	GPL14824	GSM1426644	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_5936_1255c_B	Rv1255c Possible oxidoreductase subunit	PRJNA254351	GSE59086	GPL14824	GSM1426645	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_6050_1255c_C	Rv1255c Possible oxidoreductase subunit	PRJNA254351	GSE59086	GPL14824	GSM1426646	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_8005_1255c	Rv1255c Possible oxidoreductase subunit	PRJNA254351	GSE59086	GPL14824	GSM1426647	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_4687_1267c	Rv1267c Transcriptional regulatory protein EmbR	PRJNA254351	GSE59086	GPL14824	GSM1426648	Tiling Array	RNA	25232098	4-Jul-14	GEO
TFOE_5216_1267c	Rv1267c Transcriptional regulatory protein EmbR	PRJNA254351	GSE59086	GPL14824	GSM1426649	Tiling Array	RNA	25232098	4-Jul-14	GEO