Dataset Information

The Mycobacterium tuberculosis regulatory network and hypoxia.

ABSTRACT: We have taken the first steps towards a complete reconstruction of the Mycobacterium tuberculosis regulatory network based on ChIP-Seq and combined this reconstruction with system-wide profiling of messenger RNAs, proteins, metabolites and lipids during hypoxia and re-aeration. Adaptations to hypoxia are thought to have a prominent role in M. tuberculosis pathogenesis. Using ChIP-Seq combined with expression data from the induction of the same factors, we have reconstructed a draft regulatory network based on 50 transcription factors. This network model revealed a direct interconnection between the hypoxic response, lipid catabolism, lipid anabolism and the production of cell wall lipids. As a validation of this model, in response to oxygen availability we observe substantial alterations in lipid content and changes in gene expression and metabolites in corresponding metabolic pathways. The regulatory network reveals transcription factors underlying these changes, allows us to computationally predict expression changes, and indicates that Rv0081 is a regulatory hub.

SUBMITTER: Galagan JE

PROVIDER: S-EPMC4087036 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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The Mycobacterium tuberculosis regulatory network and hypoxia.

Galagan James E JE Minch Kyle K Peterson Matthew M Lyubetskaya Anna A Azizi Elham E Sweet Linsday L Gomes Antonio A Rustad Tige T Dolganov Gregory G Glotova Irina I Abeel Thomas T Mahwinney Chris C Kennedy Adam D AD Allard René R Brabant William W Krueger Andrew A Jaini Suma S Honda Brent B Yu Wen-Han WH Hickey Mark J MJ Zucker Jeremy J Garay Christopher C Weiner Brian B Sisk Peter P Stolte Christian C Winkler Jessica K JK Van de Peer Yves Y Iazzetti Paul P Camacho Diogo D Dreyfuss Jonathan J Liu Yang Y Dorhoi Anca A Mollenkopf Hans-Joachim HJ Drogaris Paul P Lamontagne Julie J Zhou Yiyong Y Piquenot Julie J Park Sang Tae ST Raman Sahadevan S Kaufmann Stefan H E SH Mohney Robert P RP Chelsky Daniel D Moody D Branch DB Sherman David R DR Schoolnik Gary K GK

Nature 20130703 7457

We have taken the first steps towards a complete reconstruction of the Mycobacterium tuberculosis regulatory network based on ChIP-Seq and combined this reconstruction with system-wide profiling of messenger RNAs, proteins, metabolites and lipids during hypoxia and re-aeration. Adaptations to hypoxia are thought to have a prominent role in M. tuberculosis pathogenesis. Using ChIP-Seq combined with expression data from the induction of the same factors, we have reconstructed a draft regulatory ne ...[more]

PMID: 23823726

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Project description:The ability to adapt to different conditions is key for Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), to successfully infect human hosts. Adaptations allow the organism to evade the host immune responses during acute infections and persist for an extended period of time during the latent infectious stage. In latently infected individuals, estimated to include one-third of the human population, the organism exists in a variety of metabolic states, which impedes the development of a simple strategy for controlling or eradicating this disease. Direct knowledge of the metabolic states of M. tuberculosis in patients would aid in the management of the disease as well as in forming the basis for developing new drugs and designing more efficacious drug cocktails. Here, we propose an in silico approach to create state-specific models based on readily available gene expression data. The coupling of differential gene expression data with a metabolic network model allowed us to characterize the metabolic adaptations of M. tuberculosis H37Rv to hypoxia. Given the microarray data for the alterations in gene expression, our model predicted reduced oxygen uptake, ATP production changes, and a global change from an oxidative to a reductive tricarboxylic acid (TCA) program. Alterations in the biomass composition indicated an increase in the cell wall metabolites required for cell-wall growth, as well as heightened accumulation of triacylglycerol in preparation for a low-nutrient, low metabolic activity life style. In contrast, the gene expression program in the deletion mutant of dosR, which encodes the immediate hypoxic response regulator, failed to adapt to low-oxygen stress. Our predictions were compatible with recent experimental observations of M. tuberculosis activity under hypoxic and anaerobic conditions. Importantly, alterations in the flow and accumulation of a particular metabolite were not necessarily directly linked to differential gene expression of the enzymes catalyzing the related metabolic reactions.

Dataset Information

The Mycobacterium tuberculosis regulatory network and hypoxia.

Publications

The Mycobacterium tuberculosis regulatory network and hypoxia.

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