PE/PPE MTB study
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ABSTRACT:
PROVIDER: PRJEB12515 | ENA |
REPOSITORIES: ENA
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Project description:Genome-wide expression data can provide important insights into normal and pathological cellular processes. However, the ability to use gene expression data to quantitatively assess the activation state of a given signaling pathway or transcriptional network in a sensitive and specific manner remains an important unmet goal. We now describe a computational algorithm, energy-paired scoring (EPS), that satisfies these criteria by predicting pathway activity using gene-gene interactions within a pathway signature in a manner analogous to the estimation of energy generated by two charged particles, as described by Coulomb’s law. We demonstrate the ability of EPS to: quantitatively assess pathway activation levels in vivo and in vitro; accurately estimate the extent of pathway inhibition achieved by gene knockdown; sensitively detect crosstalk between endogenous signaling pathways in vivo; and accurately identify compounds capable of inhibiting selected signaling pathways. Our findings indicate that EPS can accurately predict pathway activity over a wide dynamic range based upon gene expression data sets derived from multiple profiling platforms, as well as different species, tissues and cell types in both in vitro and in vivo contexts Four timepoints (0h, 24h, 48h and 96h) with 3 replicates per timepoint of doxycycline induction for MTB (Control), MTB/TAN, MTB/TOM and MTB/TWNT1
2013-09-18 | E-GEOD-50969 | biostudies-arrayexpress
Project description:Respiratory ATP-synthesis is at present the only known mechanism for ATP synthesis in Mtb. This makes Mtb particularly vulnerable to inhibition of respiratory ATP synthase inhibitors such as TMC207, a novel compound for treatment of tuberculosis. We now provide first evidence that Mtb possesses a pathway that is fermentative in nature that could compensate lack of respiratory ATP synthesis. We identified acetate as a fermentation product in Mtb. Production of acetate was mediated by phosphotransacetylase (Pta) and acetate kinase (AckA). In acetate fermenting Mtb cultures, ATP levels remained stable despite inhibition of respiratory ATP synthase. Deletion of the PtaAckA pathway in Mtb decreased ATP content and impaired survival. This study provides evidence that in Mtb substrate level phosphorylation can compensate lack of oxidative phosphorylation, and thus facilitates survival of Mtb in the absence of respiration. Acetate fermentation contributes to adaptation to respiration-limiting conditions, and plays an important role in the emerging field of fermentative metabolism of Mtb. We performed DNA microarray analysis to validate the reduction of oxygen concentration by comparing aerobic and hypoxic cultures. RNA was prepared from Mtb after two days of cultivation in aerobic and in hypoxic cultures. At each condition, Mtb were cultured in medium supplemented with glycerol and glucose. Labelled cDNA from three independent experiments was subjected to array analysis.
2012-12-31 | E-GEOD-35484 | biostudies-arrayexpress
Project description:The principal virulence determinant of Mycobacterium tuberculosis (Mtb), the ESX-1 protein secretion system, is positively controlled at the transcriptional level by EspR. Depletion of EspR reportedly affects a small number of genes, both positively or negatively, including a key ESX-1 component, the espACD operon. EspR is also thought to be an ESX-1 substrate. Using EspR-specific antibodies in ChIP-Seq experiments (chromatin immunoprecipitation followed by ultra-high throughput DNA sequencing) we show that EspR binds to at least 165 loci on the Mtb genome. Included in the EspR regulon are genes encoding not only EspA, but also EspR itself, the ESX-2 and ESX-5 systems, a host of diverse cell wall functions, such as production of the complex lipid PDIM (phenolthiocerol dimycocerosate) and the PE/PPE cell-surface proteins. EspR binding sites are not restricted to promoter regions and can be clustered. This suggests that rather than functioning as a classical regulatory protein EspR acts globally as a nucleoid-associated protein capable of long-range interactions consistent with a recently established structural model. EspR expression was shown to be growth phase-dependent, peaking in the stationary phase. Overexpression in Mtb strain H37Rv revealed that EspR influences target gene expression both positively or negatively leading to growth arrest. At no stage was EspR secreted into the culture filtrate. Thus, rather than serving as a specific activator of a virulence locus, EspR is a novel nucleoid-associated protein, with both architectural and regulatory roles, that impacts cell wall functions and pathogenesis through multiple genes. ChIP-Seq of EspR in Mtb H37Rv at mid-log phase of growth. Two independent experiments were performed. Input DNA (No IP) was used as a control.
2012-04-02 | E-GEOD-35149 | biostudies-arrayexpress
Project description:RNA was isolated from mammary glands from 55 day old control mice, mice overexpressing the miR-200b/200a/429 cluster in mammary epithelial cells (MTB-200ba429) mice overexpressing the IGF-IR transgene in mammary epithelial cells (MTB-IGFIR), and mice overexpressing both the miR-200b/200a/429 cluster and the IGF-IR transgene in mammary epithelial cells (MTB-IGFIRba429)
2021-09-17 | GSE180264 | GEO
Project description:In this study we investigate the molecular physiology of the main S. cerevisiae commercial strain (PE-2) used on Brazilian bioethanol process under two distinct conditions: typical (TF) and flocculated (co-aggregated - FL) fermentation. Transcriptional machinery of PE-2 was assessed by high throughput sequencing-based methods (RNA-seq) during industrial fed-batch fermentations. Data from comparative analysis revealed distinct transcriptional profiles among conditions, characterized mainly by a deep gene repression on FL process.
2015-02-02 | GSE41834 | GEO
Project description:Respiratory ATP-synthesis is at present the only known mechanism for ATP synthesis in Mtb. This makes Mtb particularly vulnerable to inhibition of respiratory ATP synthase inhibitors such as TMC207, a novel compound for treatment of tuberculosis. We now provide first evidence that Mtb possesses a pathway that is fermentative in nature that could compensate lack of respiratory ATP synthesis. We identified acetate as a fermentation product in Mtb. Production of acetate was mediated by phosphotransacetylase (Pta) and acetate kinase (AckA). In acetate fermenting Mtb cultures, ATP levels remained stable despite inhibition of respiratory ATP synthase. Deletion of the PtaAckA pathway in Mtb decreased ATP content and impaired survival. This study provides evidence that in Mtb substrate level phosphorylation can compensate lack of oxidative phosphorylation, and thus facilitates survival of Mtb in the absence of respiration. Acetate fermentation contributes to adaptation to respiration-limiting conditions, and plays an important role in the emerging field of fermentative metabolism of Mtb.
2012-12-31 | GSE35484 | GEO
Project description:Increasing experimental evidence supports that Mycobacterium tuberculosis (Mtb) has evolved strategies to survive within the lysosomes from activated macrophages, which may represent a reservoir for persistent mycobacteria. To further our knowledge in Mtb response to the lysosomal environment, we profiled the global transcriptional activity of Mtb in a lysosomal in vitro exposure (LivE) model. At inhibitory conditions of lysosomal SF (iLivE), which did not kill but arrested mycobacterial replication thereby mimicking persistence, Mtb expresses a unique transcriptome, where genes involved in general stress response, metabolic reprogramming, cell wall remodeling, respiration, oxidative stress and dormancy response were found to be significantly modulated. Genes encoding for protein families involved in Mtb virulence including ESAT-6, PE-PPE and Mce proteins were also distinctly regulated. Extensive meta-analysis of the Mtb transcriptomes from iLivE and previously reported ex vivo, in vivo and in vitro stress models revealed most significant overlap between iLivE and primary murine macrophage infection model. Our study also highlighted the α-glucan synthesis pathway and a distinct set of toxin-antitoxin systems as toxicity mechanisms that could be exploited as novel antimicrobial approaches for intra-macrophage persistent bacilli. The specificity in responses generated in the LivE model was supported by the significant number of iLivE genes that did not overlap with any of the previously reported in vitro stress models. Finally, to validate the relevance of the LivE model, rv1258c encoding for the efflux pump protein Tap, was selected from the iLivE Mtb transcriptome for further characterization. An Mtb Δrv1258c mutant was constructed and displayed increased susceptibility to killing by lysosomal SF and by the antimicrobial peptide LL-37 found in lysosomes. Furthermore, Δrv1258c Mtb was attenuated in its ability to survive in primary murine macrophages.
2016-04-27 | GSE68337 | GEO