Reconstruction of lipid metabolism regulatory network in Mycobacterium tuberculosis
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Lipid metabolism plays a prominent role in the survival of Mycobacterium tuberculosis (MTB) in both the macrophage and mammalian hosts. A central question in the reconstruction of lipid metabolism in MTB is the key regulatory programs responsible for changes in this metabolism under different conditions. One of the most studied conditions is hypoxia (oxygen deprivation) as adaptations to hypoxia are thought to play an important role in MTB pathogenesis and latency. To identify temporal trends during a hypoxic time course and associate them with possible regulators, expression data was clustered into paths using DREM algorithm and available ChIP-Seq data for over 80 transcription factors (TFs). The degree to which expression patterns might reflect the direct action of transcription factors was assessed by evaluating the consistency between the path, the expression of each TF binding genes in the path, and the predicted regulatory role of the TF from the regulatory network. DosR was correctly identified as an activator of the path corresponding almost entirely to its regulon. Rv0081 was found to be a candidate high level regulator broadly predictive of the overall expression of sets of genes during hypoxia and re-aeration. An essential part of the continued survival of MTB in the host is due to its adaptation to the phagosomal compartment of the macrophage where the bacterium faces hypoxic as well as other stresses. Using the same approach and several time course expression data sets available for MTB in macrophage cultures, macrophage temporal expression models were built and compared to the hypoxia model. Similar trends were found in the expression of genes involved in respiration, cholesterol catabolism and methylcitrate cycle. In contrast, a group of genes responsible for the synthesis of complex cell wall lipids (PAT/DAT and SL-1) were up-regulated in the macrophage models and downregulated in the hypoxic model. PhoP was predicted as a potential main regulator of these genes as a result of pH change which takes place in the macrophage environment but not during hypoxia.