The Mycobacterium tuberculosis regulatory network and hypoxia

James E. Galagan (), Kyle Minch, Matthew Peterson, Anna Lyubetskaya, Elham Azizi, Linsday Sweet, Antonio Gomes, Tige Rustad, Gregory Dolganov, Irina Glotova, Thomas Abeel, Chris Mahwinney, Adam D. Kennedy, René Allard, William Brabant, Andrew Krueger, Suma Jaini, Brent Honda, Wen-Han Yu, Mark J. Hickey, Jeremy Zucker, Christopher Garay, Brian Weiner, Peter Sisk, Christian Stolte, Jessica K. Winkler, Yves Van de Peer, Paul Iazzetti, Diogo Camacho, Jonathan Dreyfuss, Yang Liu, Anca Dorhoi, Hans-Joachim Mollenkopf, Paul Drogaris, Julie Lamontagne, Yiyong Zhou, Julie Piquenot, Sang Tae Park, Sahadevan Raman, Stefan H. E. Kaufmann, Robert P. Mohney, Daniel Chelsky, D. Branch Moody, David R. Sherman and Gary K. Schoolnik
Additional contact information
James E. Galagan: Boston University
Kyle Minch: Seattle Biomedical Research Institute
Matthew Peterson: Boston University
Anna Lyubetskaya: Bioinformatics Program, Boston University
Elham Azizi: Bioinformatics Program, Boston University
Linsday Sweet: Immunology and Allergy, Brigham and Women’s Hospital and Harvard Medical School
Antonio Gomes: Bioinformatics Program, Boston University
Tige Rustad: Seattle Biomedical Research Institute
Gregory Dolganov: Stanford Medical School
Irina Glotova: Bioinformatics Program, Boston University
Thomas Abeel: The Eli and Edythe L. Broad Institute of Harvard and MIT
Chris Mahwinney: Boston University
Adam D. Kennedy: Metabolon Inc.
René Allard: Caprion Proteomics, Inc., Montreal, Quebec H4S 2C8, Canada
William Brabant: Seattle Biomedical Research Institute
Andrew Krueger: Boston University
Suma Jaini: Boston University
Brent Honda: Boston University
Wen-Han Yu: Boston University
Mark J. Hickey: Seattle Biomedical Research Institute
Jeremy Zucker: The Eli and Edythe L. Broad Institute of Harvard and MIT
Christopher Garay: Boston University
Brian Weiner: The Eli and Edythe L. Broad Institute of Harvard and MIT
Peter Sisk: The Eli and Edythe L. Broad Institute of Harvard and MIT
Christian Stolte: The Eli and Edythe L. Broad Institute of Harvard and MIT
Jessica K. Winkler: Seattle Biomedical Research Institute
Yves Van de Peer: Ghent University, 9052 Gent, Belgium
Paul Iazzetti: Boston University
Diogo Camacho: Boston University
Jonathan Dreyfuss: Boston University
Yang Liu: Stanford Medical School
Anca Dorhoi: Max Planck Institute for Infection Biology, 10117 Berlin, Germany
Hans-Joachim Mollenkopf: Microarray Core Facility, Max Planck Institute for Infection Biology, 10117 Berlin, Germany
Paul Drogaris: Caprion Proteomics, Inc., Montreal, Quebec H4S 2C8, Canada
Julie Lamontagne: Caprion Proteomics, Inc., Montreal, Quebec H4S 2C8, Canada
Yiyong Zhou: Caprion Proteomics, Inc., Montreal, Quebec H4S 2C8, Canada
Julie Piquenot: Caprion Proteomics, Inc., Montreal, Quebec H4S 2C8, Canada
Sang Tae Park: Boston University
Sahadevan Raman: Boston University
Stefan H. E. Kaufmann: Max Planck Institute for Infection Biology, 10117 Berlin, Germany
Robert P. Mohney: Metabolon Inc.
Daniel Chelsky: Caprion Proteomics, Inc., Montreal, Quebec H4S 2C8, Canada
D. Branch Moody: Immunology and Allergy, Brigham and Women’s Hospital and Harvard Medical School
David R. Sherman: Seattle Biomedical Research Institute
Gary K. Schoolnik: Stanford Medical School

Nature, 2013, vol. 499, issue 7457, 178-183

Abstract: 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.

Date: 2013
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DOI: 10.1038/nature12337

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