Ultrasensitive profiling of UV mutations in facial tumors in TSC
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PROVIDER: PRJNA836690 | ENA |
REPOSITORIES: ENA
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Project description:Ultrasensitive profiling of UV mutations in facial tumors in TSC
| PRJNA836691 | ENA
Project description:Patients with tuberous sclerosis complex (TSC) develop hamartomas containing biallelic inactivating mutations in either TSC1 or TSC2, resulting in mammalian target of rapamycin (mTOR) activation. Hamartomas overgrow epithelial and mesenchymal cells in TSC skin. The pathogenetic mechanisms for these changes had not been investigated, and the existence or location of cells with biallelic mutations (âtwo-hitâ cells) that resulted in mTOR activation was unclear. We compared TSC skin hamartomas (facial angiofibromas and periungual fibromas) to normal-appearing skin of the same patient, and observed more proliferation and mTOR activation in hamartoma epidermis. âTwo-hitâ cells were not detected in the epidermis. Fibroblast-like cells in the dermis, however, exhibited allelic deletion of TSC2, in both touch preparations of fresh tumor samples and cells grown from TSC skin tumors, suggesting that increased epidermal proliferation and mTOR activation were not caused by second-hit mutations in the keratinocytes but by mesenchymal-epithelial interactions. Gene expression arrays, used to identify potential paracrine factors released by mesenchymal cells, revealed more epiregulin mRNA in fibroblast-like angiofibroma and periungual fibroma cells than in fibroblasts from normal-appearing skin of the same patient. Elevation of epiregulin mRNA was confirmed using real-time PCR, and increased amounts of epiregulin protein were demonstrated using immunoprecipitation and ELISA. Epiregulin stimulated keratinocyte proliferation and phosphorylation of ribosomal protein S6 in vitro. These results suggest that hamartomatous TSC skin tumors are induced by paracrine factors released by âtwo-hitâ cells in the dermis, and that proliferation with mTOR activation of the overlying epidermis is an effect of epiregulin. Experiment Overall Design: The study is of case/control design with biological replication. Tumor (case) and normal (control) fibroblast cells were isolated from each of four patients (biological replicates).
2008-04-06 | E-GEOD-9715 | biostudies-arrayexpress
Project description:Patients with tuberous sclerosis complex (TSC) develop hamartomas containing biallelic inactivating mutations in either TSC1 or TSC2, resulting in mammalian target of rapamycin (mTOR) activation. Hamartomas overgrow epithelial and mesenchymal cells in TSC skin. The pathogenetic mechanisms for these changes had not been investigated, and the existence or location of cells with biallelic mutations (“two-hit” cells) that resulted in mTOR activation was unclear. We compared TSC skin hamartomas (facial angiofibromas and periungual fibromas) to normal-appearing skin of the same patient, and observed more proliferation and mTOR activation in hamartoma epidermis. “Two-hit” cells were not detected in the epidermis. Fibroblast-like cells in the dermis, however, exhibited allelic deletion of TSC2, in both touch preparations of fresh tumor samples and cells grown from TSC skin tumors, suggesting that increased epidermal proliferation and mTOR activation were not caused by second-hit mutations in the keratinocytes but by mesenchymal-epithelial interactions. Gene expression arrays, used to identify potential paracrine factors released by mesenchymal cells, revealed more epiregulin mRNA in fibroblast-like angiofibroma and periungual fibroma cells than in fibroblasts from normal-appearing skin of the same patient. Elevation of epiregulin mRNA was confirmed using real-time PCR, and increased amounts of epiregulin protein were demonstrated using immunoprecipitation and ELISA. Epiregulin stimulated keratinocyte proliferation and phosphorylation of ribosomal protein S6 in vitro. These results suggest that hamartomatous TSC skin tumors are induced by paracrine factors released by “two-hit” cells in the dermis, and that proliferation with mTOR activation of the overlying epidermis is an effect of epiregulin. Keywords: Disease state analysis
2008-03-01 | GSE9715 | GEO
Project description:We report the global gene expression effects in TSC-deficient and TSC wild type cells after treatemnet with. CDK7 inhibitor(THZ1), we performed RNA-Seq on TSC1-null HCV.29 cells and TSC1-intact HCV.29 cells treated with 30nM THZ1, and with 100nM THZ1, for 6 hours. Many genes showed marked changes in expression in comparison with control untreated cells. Furthermore, 1128 genes showed > 5-fold lower expression in 30nM THZ1-treated TSC1-null HCV.29 cells compared with 30nM THZ1-treated TSC1-intact HCV.29 cells.
2019-08-08 | GSE135527 | GEO
Project description:Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion
| PRJNA559171 | ENA
Project description:Chromatin organisation of trophoblast stem cells (TSC) were compared with that of embryonic stem cells (ESC). The method enriches Hi-C libraries, to detect promoter interactions at restriction fragment level. We prepared Hi-C libraries from TSC and ESC (serum grown) samples and enriched them with a promoter capture bait system that captures ~22.000 promoters. Promoter interactions were then analysed using the GOTHiC pipeline.
2018-09-05 | E-MTAB-6585 | biostudies-arrayexpress
Project description:Peg10 regulation of TSC differentiation
| PRJNA504005 | ENA
Project description:Somatic mutations are highly enriched at transcription factor (TF) binding sites, with the strongest trend being observed for ultraviolet light (UV)-induced mutations in melanomas. One of the main mechanisms proposed for this hyper-mutation pattern is the inefficient repair of UV lesions within TF-binding sites, caused by competition between TFs bound to these lesions and the DNA repair proteins that must recognize the lesions to initiate repair. However, TF binding to UV-irradiated DNA is poorly characterized, and it is unclear whether TFs maintain specificity for their DNA sites after UV exposure. We developed UV-Bind, a high-throughput approach to investigate the impact of UV irradiation on protein-DNA binding specificity. We applied UV-Bind to ten TFs from eight structural families, and found that UV lesions significantly altered the DNA-binding preferences of all TFs tested. The main effect was a decrease in binding specificity, but the precise effects and their magnitude differ across factors. Importantly, we found that despite the overall reduction in DNA-binding specificity in the presence of UV lesions, TFs can still compete with repair proteins for lesion recognition, in a manner consistent with their specificity for UV-irradiated DNA. In addition, for a subset of TFs we identified a surprising but reproducible effect at certain non-consensus DNA sequences, where UV irradiation leads to a high increase in the level of TF binding. These changes in DNA-binding specificity after UV irradiation, at both consensus and non-consensus sites, have important implications for the regulatory and mutagenic roles of TFs in the cell.
2023-01-20 | GSE223021 | GEO
Project description:Somatic mutations are highly enriched at transcription factor (TF) binding sites, with the strongest trend being observed for ultraviolet light (UV)-induced mutations in melanomas. One of the main mechanisms proposed for this hyper-mutation pattern is the inefficient repair of UV lesions within TF-binding sites, caused by competition between TFs bound to these lesions and the DNA repair proteins that must recognize the lesions to initiate repair. However, TF binding to UV-irradiated DNA is poorly characterized, and it is unclear whether TFs maintain specificity for their DNA sites after UV exposure. We developed UV-Bind, a high-throughput approach to investigate the impact of UV irradiation on protein-DNA binding specificity. We applied UV-Bind to ten TFs from eight structural families, and found that UV lesions significantly altered the DNA-binding preferences of all TFs tested. The main effect was a decrease in binding specificity, but the precise effects and their magnitude differ across factors. Importantly, we found that despite the overall reduction in DNA-binding specificity in the presence of UV lesions, TFs can still compete with repair proteins for lesion recognition, in a manner consistent with their specificity for UV-irradiated DNA. In addition, for a subset of TFs we identified a surprising but reproducible effect at certain non-consensus DNA sequences, where UV irradiation leads to a high increase in the level of TF binding. These changes in DNA-binding specificity after UV irradiation, at both consensus and non-consensus sites, have important implications for the regulatory and mutagenic roles of TFs in the cell.
2023-01-20 | GSE223019 | GEO
Project description:Somatic mutations are highly enriched at transcription factor (TF) binding sites, with the strongest trend being observed for ultraviolet light (UV)-induced mutations in melanomas. One of the main mechanisms proposed for this hyper-mutation pattern is the inefficient repair of UV lesions within TF-binding sites, caused by competition between TFs bound to these lesions and the DNA repair proteins that must recognize the lesions to initiate repair. However, TF binding to UV-irradiated DNA is poorly characterized, and it is unclear whether TFs maintain specificity for their DNA sites after UV exposure. We developed UV-Bind, a high-throughput approach to investigate the impact of UV irradiation on protein-DNA binding specificity. We applied UV-Bind to ten TFs from eight structural families, and found that UV lesions significantly altered the DNA-binding preferences of all TFs tested. The main effect was a decrease in binding specificity, but the precise effects and their magnitude differ across factors. Importantly, we found that despite the overall reduction in DNA-binding specificity in the presence of UV lesions, TFs can still compete with repair proteins for lesion recognition, in a manner consistent with their specificity for UV-irradiated DNA. In addition, for a subset of TFs we identified a surprising but reproducible effect at certain non-consensus DNA sequences, where UV irradiation leads to a high increase in the level of TF binding. These changes in DNA-binding specificity after UV irradiation, at both consensus and non-consensus sites, have important implications for the regulatory and mutagenic roles of TFs in the cell.
2023-01-20 | GSE223022 | GEO