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:

<p><b>BACKGROUND: </b>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.</p><p><b>RESULTS: </b>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.</p><p><b>CONCLUSION: </b>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.</p>

Supplementary Files: 
AttachmentSize
File Supplementary Excel Files for Rustad et al. 201419.36 MB
File TFOE Searchable Excel File20.15 MB

TFOE Expression Data Records

Title Gene BioProject GEO Series Platform Accession Sample Method Sample Type References Release Date Repository
TFOE_2386_1332
Rv1332
Transcriptional regulatory protein
 PRJNA254351 GSE59086 GPL14824 GSM1426656 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_7099_1332
Rv1332
Transcriptional regulatory protein
 PRJNA254351 GSE59086 GPL14824 GSM1426657 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_1701_1353c
Rv1353c
Transcriptional regulator, TetR family
 PRJNA254351 GSE59086 GPL14824 GSM1426658 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_5758_1353c
Rv1353c
Transcriptional regulator, TetR family
 PRJNA254351 GSE59086 GPL14824 GSM1426659 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_5958_1353c
Rv1353c
Transcriptional regulator, TetR family
 PRJNA254351 GSE59086 GPL14824 GSM1426660 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_2892_1358
Rv1358
Adenylyl cyclase class-3/4/guanylyl cyclase / Disease resistance domain-containing protein / Tetratricopeptide repeat-containing protein / Transcriptional regulator, LuxR family
 PRJNA254351 GSE59086 GPL14824 GSM1426661 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_8006_1358
Rv1358
Adenylyl cyclase class-3/4/guanylyl cyclase / Disease resistance domain-containing protein / Tetratricopeptide repeat-containing protein / Transcriptional regulator, LuxR family
 PRJNA254351 GSE59086 GPL14824 GSM1426662 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_9428_1358
Rv1358
Adenylyl cyclase class-3/4/guanylyl cyclase / Disease resistance domain-containing protein / Tetratricopeptide repeat-containing protein / Transcriptional regulator, LuxR family
 PRJNA254351 GSE59086 GPL14824 GSM1426663 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_3603_1359
Rv1359
Adenylyl cyclase class-3/4/guanylyl cyclase
 PRJNA254351 GSE59086 GPL14824 GSM1426664 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_2884_1287
Rv1287
Predicted transcriptional regulator of sulfate adenylyltransferase, Rrf2 family
 PRJNA254351 GSE59086 GPL14824 GSM1426653 Tiling Array RNA 25232098 4-Jul-14 GEO