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
RhCMV-TB Metabolomics Data Metabolomics 2018
RhCMV-TB Proteomics Data Protein 2018
RhCMV-TB Transcriptomic Data RNA-seq RNA 2018
RhCMV-TB Meta Data in progress NA NA Meta-data in preparation 2018 in progress
TFOE_8468_3911
Rv3911
RNA polymerase sigma-70 factor, ECF subfamily
 PRJNA254351 GSE59086 GPL14824 GSM1427062 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_8127_3911
Rv3911
RNA polymerase sigma-70 factor, ECF subfamily
 PRJNA254351 GSE59086 GPL14824 GSM1427061 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_2756_3911
Rv3911
RNA polymerase sigma-70 factor, ECF subfamily
 PRJNA254351 GSE59086 GPL14824 GSM1427060 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_7945_3862c_B
Rv3862c
Transcriptional regulator WhiB-like WhiB6
 PRJNA254351 GSE59086 GPL14824 GSM1427059 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_6830_3862c
Rv3862c
Transcriptional regulator WhiB-like WhiB6
 PRJNA254351 GSE59086 GPL14824 GSM1427058 Tiling Array RNA 25232098 4-Jul-14 GEO
TFOE_4985_3862c_A
Rv3862c
Transcriptional regulator WhiB-like WhiB6
 PRJNA254351 GSE59086 GPL14824 GSM1427057 Tiling Array RNA 25232098 4-Jul-14 GEO