The effect of EZH2 knockdown on gene expression in KDM6A-deficient KYSE180 cells following exposure to ionizing radiation [RNA-seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE264079 | GEO | 2024/04/22
REPOSITORIES: GEO
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Project description:We report a heterogeneous cellular response to IR by single cell transcriptome sequencing utilizing the modified Smart-seq2 technology in cultured MDA-MB-231 cells. Single cell tSNE clustering analysis showed four distinctive clusters of cells. And in the absence of the ATM kinase, cells displayed much less transcriptional changes after IR. We also selected three detected IR-induced genes for functional validation to confirm their importance in radiosensitivity.
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Project description:Cells differ in their response to ionizing radiation (IR) depending on the cell type, proliferation rate and cell cycle stage. Normal stem cells exhibit a radiosensitive phenotype contributing to normal tissue injury following radiotherapy, whereas differentiated cells are comparably resistant to IR-induced programmed cell death. An improved understanding of differential radiation responses in varying cellular contexts and their mechanistic distinction is imperative for efficient treatment of malignancies by radiotherapy. Low dose IR induced apoptosis is exclusively confined to the normal stem cells in multiple stem cell niches in vivo and the radiation hypersensitivity is recapitulated in primary stem cell culture models of embryonic and neuronal stem cells contrasting their isogenic differentiated non-stem radioresistant progeny. Transcriptional profiles of primary, early passage, mouse embryonic stem cells and isogenic differentiated non-stem cells were compared to discover genes that are selectively induced in stem cells, but not in differentiated cells; to characterize potential molecular regulators of stem cell radiosensitivity. These molecular insights may contribute to the development of therapeutics that minimize normal tissue injury.
2018-07-31 | GSE44780 | GEO
Project description:Ionizing radiation (IR) is associated with thrombotic vascular occlusion. Thrombosis in malignancy predicts a poor clinical outcome. Tissue factor (TF) is the initiator of the extrinsic co-agulation system and induces thrombus formation. Our study examined whether IR induced TF expression and procoagulability in the myelomonocytic leukemia THP-1 cell model. We further investigated coordinated gene alterations associated with TF upregulation and IR-induced thrombogenicity. Gene expression profiling revealed IR to increase the expression of inflammatory and apoptosis-related pathways, contributing to TF upregulation and increased TF procoagulability on day 7 post IR. The upregulation of these pathways together with TF upregulation contributed to the increased thrombogenic potential of tissues post application of IR. Keywords: irridiation response
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Project description:Accidents with ionizing radiation (IR) often involve acute high dose exposures that can lead to acute radiation syndrome and late effects. IR can induce genomic lesions, cell death or carcinogenesis. Here, we investigated acute IR-induced cellular genomic signatures at the genome wide level. After exposing the adenocarcinoma cell line A549 to an acute 6 Gy 240 kV X-Ray dose, four surviving clonogenic cells were recovered by minimal dilution and further expanded and analyzed by cytogenetics, chromosome painting and tiling-path array CGH, with the non-irradiated clone0 serving as control. It was found that acute X-ray exposure induced changes in modal chromosome number and specific translocations in the four irradiation surviving clones. Furthermore, clone4 displayed an increased radiosensitivity at D > 5 Gy. Array CGH disclosed unique and recurrent genomic changes, predominantly gains, and disclosed fragile sites FRA3B and FRA16D as preferential regions of genomic alterations in all irradiated clones, which likely relates to irradiation-induced genomic stress. Gene expression analysis revealed a specific profile of 364 genes in clone4, of which p53 pathway genes may contribute to its increased radiosensitivity. IR-induced genomic changes AND fragile site expression highlight the capacity of a single acute radiation exposure to resculpture the genome of tumor cells by inflicting genomic stress. Gene expression in A549 cell line was analysed after exposure to 6Gy X-rays at a dose rate of 1Gy/min.
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Project description:Increased use of nuclear reactors and radioactive materials for energy production and proliferation of nuclear weaponry increases risk of radiation exposure or nuclear accidents. Development of radiation countermeasures for the diagnosis, prognosis, and radiation treatment are trailing behind, and knowledge of the deleterious radiation effects on health and responses to exposure at the molecular, cellular, and systems biology level are still not fully understood. In this work, skin biopsies collected at h2, d4, d7, d21, and d28 from mice exposed to 1, 3, 6, 20Gy of whole-body x-ray ionizing radiation were used in a transcriptomic approach to evaluate the potential of radiation-induced transcriptional alterations in diagnosis and prognosis of a radiation event. Mice exposed to 20Gy were euthanized under the humane endpoint of an IACUC approved study protocol at d7 while mice that received 1, 3, 6Gy survived the full 28 days time course. Sammon plot analysis showed a clear separation of samples based on survival and timepoints within lethal (20Gy) and in the sublethal (1, 3, 6Gy) IR doses. Differences in the numbers, regulation mode, and fold change of significantly differentially transcribed genes (SDTGs, p < 0.05 and FC > 2) were identified between lethal and sublethal doses. Down and upregulation dominated transcriptomes during the first post-exposure week, respectively. Numbers of SDTGs and percentages of upregulated SDTGs revealed stationary transcription and low upregulation percentages after lethal dose in contrary to transcription responses that were dynamic and largely upregulated after exposure to sublethal doses. Longitudinal variations in numbers of up/downregulated SDTGs suggested delayed and extended responses with increasing IR doses in the sublethal range with lethal-like responses in late time points suggesting more than a single-phase response. This was supported further by the distributions of common and unique genes across the TPs within each dose. Several genes with potential use as markers for radiation exposure and dosimetric applications were identified. Pathways enrichment analysis showed strong modulations of immune responses, fibrosis development, detoxification responses, hematological responses, skin reactions, neurological system disruptions, maintenance of gastric mucosa, and cell survival, migration, and proliferation pathways. The majority of the identified pathways were predicted activated after sublethal and inactivated after lethal exposures, particularly during the first post-exposure week.
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Project description:Recent studies have shown that proteins unique to tardigrades are involved in the remarkable ability of these small animals to withstand desiccation and ionizing radiation (IR). For resistance to IR, only one tardigrade unique protein has been identified so far: Dsup, for DNA damage suppressor, found in R. varieornatus and H. exemplaris. Rv-Dsup protects from DNA damage by X-rays in human cells, suggesting that DNA protection is important for resistance to IR. Here, we chose to investigate the role of DNA repair and search for novel tardigrade unique genes involved in resistance to IR. For this, we performed an unbiased proteome analysis of H. exemplaris either untreated, or at 4h post-irradiation, 24h post-irradiation and after Bleomycin treatment.
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Project description:This article highlights the radiation induced cytotoxic effect of the BCL2 inhibitor, venetoclax, in diffuse midline gliomas (DMG). 1. RNA-seq: We performed bulk RNA sequencing of DMG cells exposed to 6Gy radiation and found the genes upregulated after radiation compared to unirradiated controls. 2. DNA Repair shRNA screen: We also performed a DNA Repair shRNA screen and identified the genes which are responsible for radioresistance in DMG.
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Project description:The DNA damage response network modulates a wide array of signaling pathways, including DNA repair, cell cycle checkpoints, apoptotic pathways and numerous stress signals. The ATM protein kinase, functionally missing in patients with the human genetic disorder ataxia-telangiectasia (A-T), is a master regulator of this network when the inducing DNA lesions are double strand breaks. The ATM gene is also frequently mutated in sporadic cancers of lymphoid origin. Here, we applied a functional genomics approach that combines gene expression profiling and computational promoter analysis to obtain global dissection of the transcriptional response to ionizing radiation (IR) in murine lymphoid tissue. Cluster analysis revealed six major expression patterns in the data. Prominent among them was a gene cluster that contained dozens of genes whose response to irradiation was Atm-dependent. Computational analysis identified significant enrichment of the binding site signatures of the transcription factors NF-kB and p53 among promoters of these genes, pointing to the major role of these two transcription factors in mediating the Atm-dependent transcriptional response in the irradiated lymphoid tissue. Examination of the response showed that pro- and anti-apoptotic signals were simultaneously induced, with the pro-apoptotic pathway mediated by p53, and the pro-survival pathway by NF-kB. These findings further elucidate the molecular network induced by IR and have implications for cancer management as they suggest that a combined treatment that restores the p53-mediated apoptotic arm while blocking the NF-kB-mediated pro-survival arm could be most successful in increasing the radiosensitivity of lymphoid tumors.
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