The Mycobacterium tuberculosis regulatory network and hypoxia

Galagan, James E.; Minch, K; Peterson, Michael; Lyubetskaya, Anna; Azizi, Elham; Sweet, Linsday; Gomes, António; Rustad, Tige R.; Dolganov, Gregory; Glotova, Irina; Abeel, Thomas; Mahwinney, Chris; Kennedy, Adam D.; Allard, René; Brabant, William; Krueger, Andrew S; Jaini, Suma; Honda, Brent; Yu, Wenhan; Hickey, Mark J.; Zucker, Jeremy; Garay, Christopher; Weiner, Brian; Sisk, Peter; Stolte, Christian; Winkler, Jessica K.; Peer, Yves Van de; Iazzetti, Paul; Camacho, Diogo M.; Dreyfuss, Jonathan M.; Liu, Yang; Dorhoi, Anca; Mollenkopf, Hans-Joachim; Drogaris, Paul; Lamontagne, Julie; Zhou, Yongxia; Piquenot, Julie; Park, Sang Tae; Raman, Sahadevan; Kaufmann, Stefan H. E.; Mohney, Robert P.; Chelsky, Daniel; Moody, D. Branch; Sherman, David R.; Schoolnik, Gary K.

doi:10.1038/nature12337

Cited by 409 publications

(595 citation statements)

References 45 publications

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“…Again, the transition from a metabolically active state to a dormant state is dysregulated within Mtb: ⌬Rv2745c. Of particular note, fas and accD4, which are involved in lipid metabolism, are shown to be down-regulated upon hypoxic conditions, which we also found within our study (7).…”

Section: Volume 290 • Number 4 • January 23 2015supporting

confidence: 73%

The Mycobacterium tuberculosis Clp Gene Regulator Is Required for in Vitro Reactivation from Hypoxia-induced Dormancy

McGillivray

Golden

Kaushal

2015

Journal of Biological Chemistry

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Section: Volume 290 • Number 4 • January 23 2015supporting

confidence: 73%

The Mycobacterium tuberculosis Clp Gene Regulator Is Required for in Vitro Reactivation from Hypoxia-induced Dormancy

McGillivray

Golden

Kaushal

2015

Journal of Biological Chemistry

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“…Previous ChIP-Seq and transcriptome analysis of Mycobacterium tuberculosis have clearly demonstrated that novel and functionally relevant binding sites can be identified with high frequency in the relatively large number of smaller ChIP-Seq peaks (Galagan et al, 2013;Gao et al, 2012). Given this precedent, the numerous new candidate targets (particularly those containing instances of MC-Motif 1 and MC-Motif 2; Fig.…”

Section: Discussionmentioning

confidence: 99%

Identification of an archaeal mercury regulon by chromatin immunoprecipitation

et al. 2015

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Mercury is a heavy metal and toxic to all forms of life. Metal exposure can invoke a response to improve survival. In archaea, several components of a mercury response system have been identified, but it is not known whether metal transport is a member of this system. To identify such missing components, a peptide-tagged MerR transcription factor was used to localize enriched chromosome regions by chromosome immunoprecipitation combined with DNA sequence analysis. Such regions could serve as secondary regulatory binding sites to control the expression of additional genes associated with mercury detoxification. Among the 31 highly enriched loci, a subset of five was pursued as potential candidates based on their current annotations. Quantitative reverse transcription-PCR analysis of these regions with and without mercury treatment in WT and mutant strains lacking merR indicated significant regulatory responses under these conditions. Of these, a Family 5 extracellular solute-binding protein and the MarR transcription factor shown previously to control responses to oxidation were most strongly affected. Inactivation of the solute-binding protein by gene disruption increased the resistance of mutant cells to mercury challenge. Inductively coupled plasma-MS analysis of the mutant cell line following metal challenge indicated there was less intracellular mercury compared with the isogenic WT strain. Together, these regulated genes comprise new members of the archaeal MerR regulon and reveal a cascade of transcriptional control not previously demonstrated in this model organism.

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“…Galagan et al carried out proteome profiling of dormant and re-aerated MTB using a defined hypoxia model, and identified a total of approximately one thousand proteins (26). The process of reactivation of MTB from dormancy is a critical step in the development of active TB.…”

mentioning

confidence: 99%

Profiling the Proteome of Mycobacterium tuberculosis during Dormancy and Reactivation

Gopinath

Raghunandanan

Gomez

et al. 2015

Molecular & Cellular Proteomics

114

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Tuberculosis, caused by Mycobacterium tuberculosis, still remains a major global health problem. The main obstacle in eradicating this disease is the ability of this pathogen to remain dormant in macrophages, and then reactivate later under immuno-compromised conditions. The physiology of hypoxic nonreplicating M. tuberculosis is well-studied using many in vitro dormancy models. However, the physiological changes that take place during the shift from dormancy to aerobic growth (reactivation) have rarely been subjected to a detailed investigation. In this study, we developed an in vitro reactivation system by re-aerating the virulent laboratory strain of M. tuberculosis that was made dormant employing Wayne's dormancy model, and compared the proteome profiles of dormant and reactivated bacteria using label-free onedimensional LC/MS/MS analysis. The proteome of dormant bacteria was analyzed at nonreplicating persistent stage 1 (NRP1) and stage 2 (NRP2), whereas that of reactivated bacteria was analyzed at 6 and 24 h post reaeration. Proteome of normoxially grown bacteria served as the reference. In total, 1871 proteins comprising 47% of the M. tuberculosis proteome were identified, and many of them were observed to be expressed differentially or uniquely during dormancy and reactivation. The number of proteins detected at different stages of dormancy (764 at NRP1, 691 at NRP2) and reactivation (768 at R6 and 983 at R24) was very low compared with that of the control (1663). The number of unique proteins identified during normoxia, NRP1, NRP2, R6, and R24 were 597, 66, 56, 73, and 94, respectively. We analyzed various biological functions during these conditions. Fluctuation in the relative quantities of proteins involved in energy metabolism during dormancy and reactivation was the most significant observation we made in this study. Proteins that are up-regulated or uniquely expressed during reactivation from dormancy offer to be attractive targets for therapeutic intervention to

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The Mycobacterium tuberculosis regulatory network and hypoxia

Cited by 409 publications

References 45 publications

The Mycobacterium tuberculosis Clp Gene Regulator Is Required for in Vitro Reactivation from Hypoxia-induced Dormancy

The Mycobacterium tuberculosis Clp Gene Regulator Is Required for in Vitro Reactivation from Hypoxia-induced Dormancy

Identification of an archaeal mercury regulon by chromatin immunoprecipitation

Profiling the Proteome of Mycobacterium tuberculosis during Dormancy and Reactivation

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