The Mycobacterium tuberculosis regulatory network and hypoxia.

We have taken the first steps towards a complete reconstruction of the Mycobacterium tuberculosis (MTB) regulatory network based on ChIP-Seq and combined this reconstruction with system-wide profiling of mRNAs, proteins, metabolites and lipids during hypoxia and re-aeration. Adaptations to hypoxia are thought to play a prominent role in MTB 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 (TFs). 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 TFs underlying these changes, allows us to computationally predict expression changes, and suggests Rv0081 as a regulatory hub.

Galagan, J. E., Minch, K., Peterson, M., Lyubetskaya, A., Azizi, E., Sweet, L., Gomes, A., Rustad, T., Dolganov, G., Glotova, I., Abeel, T., Mahwinney, C., Kennedy, A. D., Allard, R., Brabant, W., Krueger, A., Jaini, S., Honda, B., Yu, W., Hickey, M. J., Zucker, J., Garay, C., Weiner, J., Sisk, P., Stolte, C., Winkler, J. K., Van de Peer, Y., Iazzetti, P., Camacho, D.M., Dreyfuss, J., Liu, Y., Dorhoi, A., Mollenkopf, H., Drogaris, P., Lamontagne, J., Zhou, K., Piquenot, J., Tae Park, S., Raman, S., H.E. Kaufmann, S., P. Mohney, R., Chelsky, D., Branch Moody, D., R. Sherman, D., K. Schoolnik, G. (2013) The Mycobacterium tuberculosis regulatory network and hypoxia. Nature 499(7457):178-83.

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