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Genetic and epigenetic changes in clonal descendants of irradiated human fibroblasts [strain 2]

ABSTRACT: To study delayed genetic and epigenetic radiation effects, which may trigger radiation-induced carcinogenesis, we have established single-cell clones from irradiated and non-irradiated primary human fibroblasts. Stable clones were endowed with the same karyotype in all analyzed metaphases after 20 population doublings (PDs), whereas unstable clones displayed mosaics of normal and abnormal karyotypes. To account for differences in radiation sensitivity, all experiments were performed with two different embryonic fibroblast strains. After a single dose of 2 Gray more than half of the irradiated clones exhibited radiation-induced genomic instability (RIGI). Methylation arrays identified several hundred differentially methylated genes and nine enriched pathways associated with in vitro ageing. Methylation changes in 259 genes and the MAP kinase signaling pathway were associated with delayed radiation effects (after 20 PDs). Collectively, our results suggest that both genetic and epigenetic changes occur in the progeny of exposed cells that were not damaged directly by irradiation, likely contributing to radiation-induced carcinogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE112873 | GEO | 2018/04/10

REPOSITORIES: GEO

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Genetic and epigenetic changes in clonal descendants of irradiated human fibroblasts [strain 1]

Project description:To study delayed genetic and epigenetic radiation effects, which may trigger radiation-induced carcinogenesis, we have established single-cell clones from irradiated and non-irradiated primary human fibroblasts. Stable clones were endowed with the same karyotype in all analyzed metaphases after 20 population doublings (PDs), whereas unstable clones displayed mosaics of normal and abnormal karyotypes. To account for differences in radiation sensitivity, all experiments were performed with two different embryonic fibroblast strains. After a single dose of 2 Gray more than half of the irradiated clones exhibited radiation-induced genomic instability (RIGI). Methylation arrays identified several hundred differentially methylated genes and nine enriched pathways associated with in vitro ageing. Methylation changes in 259 genes and the MAP kinase signaling pathway were associated with delayed radiation effects (after 20 PDs). Collectively, our results suggest that both genetic and epigenetic changes occur in the progeny of exposed cells that were not damaged directly by irradiation, likely contributing to radiation-induced carcinogenesis.

2018-04-07 | GSE112812 | GEO

Targeting HIF-2α in skeletal progenitors and their descendants for the radioprotection of bone

Project description:Radiotherapy continues to be a common treatment modality for cancer despite skeletal complications. Currently, there are no effective treatments for radiation-induced bone loss. Radiation induces substantial changes to the bone microenvironment; however, the effects of these changes on skeletal progenitors and their descendants remain elusive. Following radiation, LeprCre skeletal progenitors and their descendants, localize to hypoxic regions and exhibit HIF-2α stabilization, thus implicating a role for HIF-2α in radiation-induced bone loss. To test whether HIF-2α deficiency rescues radiation-induced bone loss, we conditionally ablated HIF-2α in LeprCre-expressing cells and their descendants. Compared to irradiated controls, irradiated LeprCre;Hif-2αfl/fl knock out mice demonstrate increased bone mass with values comparable to non-irradiated animals. Mechanistically, HIF-2α negatively regulates osteoblastogenesis, mineralization, and number of skeletal progenitors. To test whether HIF-2α can be targeted therapeutically, we administered PT2399, a potent and selective HIF-2α inhibitor whose structural analog belzutifan, has recently received FDA approval. Administration of PT2399 was sufficient to prevent radiation-induced bone loss in a single-limb irradiation model. As ~90% of patients on HIF-2α inhibitor treatment develop anemia, we constructed a PT2399-loaded bone-targeting nanocarrier (Aln-PT-NC) to increase on-target efficacy and reduce off-target kidney toxicity. Delivery of Aln-PT-NC completely prevented radiation-induced bone loss while reducing drug accumulation in the kidney. In this study, we identify HIF-2α as a negative regulator of bone formation in LeprCre skeletal progenitors and their descendants following radiotherapy and developed a bone-targeting HIF-2α therapeutic. Together, these studies highlight the clinical potential of Aln-PT-NC to be translated into a treatment regimen for bone radioprotection.

2023-06-24 | GSE235292 | GEO

Acute high dose X-irradiation-induced genomic changes in a lung tumor cell line

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.

2011-02-04 | GSE24876 | GEO

Acute high dose X-irradiation-induced genomic changes in a lung tumor cell line

2011-02-04 | E-GEOD-24876 | biostudies-arrayexpress

PBAF loss leads to DNA damage induced inflammatory signalling through defective G2/M checkpoint maintenance

Project description:PBRM1 deficiency in immortalised fibroblast cell line 1BR3-hTERT after ionising radiation treatment leads to more mitotic progression and more formation of micronucleated cells. Here, we performed total RNA-seq in 1BR3-hTERT parental line and PBRM1 knockout clones (PBRM1 KO3&KO5) under untreated (UT) or 48 hr post 6Gy irradiation condition. We found that the annotated DREAM complex target genes are less transcriptionally repressed in the 1BR3-hTERT PBRM1 knockout clones compared to the parental line after ionising radiation treatment. The results confirm our findings that PBRM1 deficiency leads to delayed p21 induction and delayed p130 hypo-phosphorylation, which leads to defective DREAM target gene repression and misregulated G2/M progression after ionising radiation treatment.

2022-09-07 | GSE183688 | GEO

Testing for gene expression differences between chromosomally stable and unstable isogenic clones

Project description:An irradiated but chromosomally stable CHO clone RT210B was used a reference to find differences in gene expression compared to radiation-induced chromosomally unstable isogenic clones. Equal quantities of two unstable different unstable clones were mixed prior to RNA extraction. Each mixture was tested twice versus the stable reference clone. Two different two clone mixtures were tested against the same chromosomally stable clone Keywords: repeat sample

2004-08-01 | GSE1626 | GEO

Transcriptional profiling of neoplastically transformed and wild type wing imaginal discs of Drosophila

Project description:In Drosophila, homozygosity for tumor suppressors, like lethal giant larvae, lgl, results in neoplastic transformation of imaginal disc epithelium - characterized by loss of their apico-basal polarity, unrestricted growth and invasion into neighboring tissues/organs. In genetic mosaics, however, lgl mutant clones are eliminated shortly after their initiation by cell competition. On the other hand, lgl mutant clones generated in Minute (M) genetic background, which compromises cell competition from the neighboring wild type cells, display clonal progression and tissue invasion. To gain insight into the molecular players of fly tumorigensis we undertook genome-wide transcriptional profiling of neoplastically transformed mosaic wing imaginal discs where lgl- clones were induced in M genetic background. Mosaic wing imaginal discs carrying wild type (lgl+) clones, also generated in M genetic background, served as controls. Transcriptional profile revealed up-regulation of a number of signaling pathways, such as Hippo, Wnt, TGF-beta or EGFR. Transcriptional profile of lgl- mosaic imaginal discs therefore provides a useful resource for identification of genes/pathways that are functionally relevant for carcinogenesis

2011-06-08 | E-MEXP-2753 | biostudies-arrayexpress

Wound response in fs-THz-irradiated mouse skin

Project description:Terahertz (THz) technology has emerged for biomedical applications such as scanning, molecular spectroscopy, and medical imaging. However, the biological effect of THz radiation is not fully understood. Non-thermal effects of THz radiation were investigated by applying a femtosecond-terahertz (fs-THz) pulse to mouse skin. Analysis of the genome-wide expression profile in fs-THz-irradiated skin indicated that wound responses were predominantly through NF?B1- and Smad3/4-mediated transcriptional activation. Repeated fs-THz radiation delayed the closure of mouse skin punch wounds due to up-regulation of transforming growth factor-beta (TGF-?). These findings suggest that fs-THz radiation provokes a wound-like signal in skin with increased expression of TGF-? and activation of its downstream target genes, which perturbs the wound healing process in vivo. To identify non-thermally induced in vivo mode action of THz radiation, gene expression profile of fs-THz-irradiated skin (at post 24-hours after 1 hour exposure) was explored. Purified total RNAs from independent 3 mice of each sham and THz group were labeled and hybridized on the Mouse Gene 1.0 ST Array (Affymetrix, Santa Clara, CA), according to manufacturer's standard protocol. Statistically filtered THz-responsive genes were examined for possible interactions with other molecules, canonical signaling pathways, and bio-functions.

2013-02-26 | E-GEOD-44671 | biostudies-arrayexpress

Gene expression profiles of radiation-induced hepatocellular carcinoma (HCC) in C3H mice

Project description:Analysis of whole transcriptome gene expression in 6 groups of liver samples in mice: HCC induced by high-LET radiation, HCC induced by low-LET radiation, spontaneous HCC, non-tumor liver irradiated with high-LET radiation, non-tumor liver irradiated with low-LET radiation, normal liver without radiation.

2021-07-14 | GSE166653 | GEO

Wound response in fs-THz-irradiated mouse skin

2013-02-26 | GSE44671 | GEO

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