Mitochondrial oxidative transport is inhibited by NDUFA4L2 to promote primary tumor escape [ATAC-Seq]
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ABSTRACT:
PROVIDER: PRJNA1260555 | ENA |
REPOSITORIES: ENA
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Project description:Mitochondrial oxidative transport is inhibited by NDUFA4L2 to promote primary tumor escape [RNA-Seq]
| PRJNA1260557 | ENA
Project description:Metastases cause most cancer deaths and reflect cellular transitions from epithelial to mesenchymal states (EMT) that enable primary tumor escape to seeding and growth at metastatic sites. Rare cancer-driving mutations that disrupt mitochondrial oxidative metabolism (OxPhos) can promote EMT, yet molecular mechanisms that more broadly link metabolism to metastases are uncertain. Analyses of clear cell renal cell carcinoma (RCC) cells identified the hypoxia-induced mitochondrial electron transport inhibitor, NDUFA4L2, as highly enriched in cancer cells with EMT signatures. NDUFA4L2 suppressed OxPhos, altering levels of metabolites that govern chromatin accessibility of EMT-related loci. NDUFA4L2 specifically promoted cell escape from primary orthotopic RCC rather than colonization to drive lung metastasis. These results demonstrate OxPhos inhibition by NDUFA4L2 is essential for RCC cells undergoing EMT to escape primary tumors.
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Project description:Metastases cause most cancer deaths and reflect cellular transitions from epithelial to mesenchymal states (EMT) that enable primary tumor escape to seeding and growth at metastatic sites. Rare cancer-driving mutations that disrupt mitochondrial oxidative metabolism (OxPhos) can promote EMT, yet molecular mechanisms that more broadly link metabolism to metastases are uncertain. Analyses of clear cell renal cell carcinoma (RCC) cells identified the hypoxia-induced mitochondrial electron transport inhibitor, NDUFA4L2, as highly enriched in cancer cells with EMT signatures. NDUFA4L2 suppressed OxPhos, altering levels of metabolites that govern chromatin accessibility of EMT-related loci. NDUFA4L2 specifically promoted cell escape from primary orthotopic RCC rather than colonization to drive lung metastasis. These results demonstrate OxPhos inhibition by NDUFA4L2 is essential for RCC cells undergoing EMT to escape primary tumors.
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Project description:We found that mitochondrial oxidative phosphorylation (OXPHOS) plays a critical role in Th17 lineage specification. CD4 T cells differentiated under OXPHOS inhibited conditions show altered metabolic gene profiles (mitochondrial function, glycolysis, and TCA cycle) and pathways associated with cell proliferation. Furthermore, gene set enrichment analysis (GSEA) revealed that mitochondrial respiration impacts transcriptional profiles related to Th17 pathogenic signatures and BATF-sensitive gene clusters. Our study reveals a regulatory role of mitochondrial OXPHOS in transcriptional programming of Th17 lineage commitment.
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Project description:In order to explore the potential role of escape of late apoptosis in metastasis, we induced apoptosis and subsequently inhibited the death process in a primary culture of colon cancer cells. Here we wanted to explore the transcriptome of such "undead" cells 7 days after apoptosis induction.
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Project description:Mitochondrial fatty acid synthesis coordinates mitochondrial oxidative metabolism
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Project description:X chromosome inactivation (XCI) silences most genes on one X chromosome in female mammals, but some genes escape XCI. To identify escape gene in vivo and to explore molecular mechanisms that regulate this process we analyzed the allele-specific expression and chromatin structure of X-linked genes in mouse tissues and cells with skewed XCI and distinguishable alleles based on single nucleotide polymorphisms. Using a new method to estimate allelic expression, we demonstrate a continuum between complete silencing and significant expression from the inactive X (Xi). Few genes (2-3%) escape XCI to a significant level and only a minority differs between mouse tissues, suggesting stringent silencing and escape controls. Allelic profiles of DNase I hypersensitivity and RNA polymerase II occupancy of genes on the Xi correlate with escape from XCI. Allelic binding profiles of the DNA binding protein CCCTC-binding factor (CTCF) in different cell types indicate that CTCF binding at the promoter correlates with escape. Importantly, CTCF binding at the boundary between escape and silenced domains may prevent the spreading of active escape chromatin into silenced domains. Examination of allelic expression in mouse hybrid tissues.
2015-02-20 | E-GEOD-59777 | biostudies-arrayexpress
Project description:X chromosome inactivation (XCI) silences most genes on one X chromosome in female mammals, but some genes escape XCI. To identify escape gene in vivo and to explore molecular mechanisms that regulate this process we analyzed the allele-specific expression and chromatin structure of X-linked genes in mouse tissues and cells with skewed XCI and distinguishable alleles based on single nucleotide polymorphisms. Using a new method to estimate allelic expression, we demonstrate a continuum between complete silencing and significant expression from the inactive X (Xi). Few genes (2-3%) escape XCI to a significant level and only a minority differs between mouse tissues, suggesting stringent silencing and escape controls. Allelic profiles of DNase I hypersensitivity and RNA polymerase II occupancy of genes on the Xi correlate with escape from XCI. Allelic binding profiles of the DNA binding protein CCCTC-binding factor (CTCF) in different cell types indicate that CTCF binding at the promoter correlates with escape. Importantly, CTCF binding at the boundary between escape and silenced domains may prevent the spreading of active escape chromatin into silenced domains. Examination of CTCF and RNA PolIIS5p occupancy in mouse hybrid cells and adult tissues.
2015-02-20 | E-GEOD-59778 | biostudies-arrayexpress
Project description:Sustained smouldering, or low grade, activation of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis. Distinct metabolic and mitochondrial features of myeloid cells guide diverse functional states. How these features act to perpetuate neuroinflammation is currently unknown. Using a multiomics approach, we identify a new molecular signature that perpetuates the activation of microglia by the reverse electron transport through complex I and the subsequent production of reactive oxygen species. Blocking reverse electron transport in pro-inflammatory myeloid cells protects against neurotoxic damage and improves functional outcomes in animal disease models in vivo. Our data show that reverse electron transport in myeloid cells is a potential new therapeutic target to foster neuroprotection in smouldering inflammatory central nervous system diseases.
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Project description:There has been increasing interest in the quantification and characterization of messages and proteins at the synapse, due to its importance in neurodegenerative disease, most notably Alzheimer’s disease. Here, we report the transcriptomic and proteomic changes that occur in synaptosomes from frontal cortices of Sod2 null mice. Constitutively null Sod2 mice were differentially dosed with the synthetic catalytic antioxidant EUK-189, which can extend the lifespan of these mice, as well as uncover or prevent neurodegeneration due to endogenous oxidative stress. This approach facilitated insight into quantification of trafficked messages and proteins to the synaptosome. We used two complementary methods to investigate the nature of the synaptosome under oxidative stress; either whole genome gene expression microarrays or mass spectrometry-based proteomics using isobaric tagging for relative and absolute quantitation (iTRAQ) of proteins. We have characterized the relative enrichments of gene ontologies at both gene and protein expression that occur due to mitochondrial oxidative stress in the synaptosome, which may lead to new avenues of investigation in understanding the regulation of the synaptic function in normal and diseased states. As a result of using these approaches, we report for the first time an activation of the mTOR pathway in synaptosomes isolated from Sod2 null mice, confirmed by an upregulation of the phosphorylation of 4E-BP1. mRNA was extracted from synaptosome samples of individual mice from each genotype/treatment group (N=9-11 per group/treatment). 200ng of the purified total RNA was then amplified one round using Ambion’s Illumina RNA Amplification Kit, to prepare cRNA for labeling and hybridization to Illumina’s MouseRef-8 v2.0 expression bead chips as per the manufacturers instructions (Illumina, San Diego, CA, USA).
2012-07-16 | E-GEOD-39372 | biostudies-arrayexpress