Similar Datasets
Project description:ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and IDH-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We found that ATRX binds regulatory elements of cell cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to early release of G2/M entry after irradiation. ATRX-deficient cells exhibit enhanced activation of master cell cycle regulator ATM with irradiation. Mice intra-cranially implanted with ATRX-deficient GBM cells demonstrate doubling of median survival compared to the ATRX-Wild Type controls when treated with ATM inhibitor AZD0156 and radiation. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display epigenetic dysregulation of cell cycle phase transitions, which opens a new window for therapies targeting this unique phenotype.
2022-01-18 | GSE178114 | GEO
Project description:ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and IDH-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We found that ATRX binds regulatory elements of cell cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to early release of G2/M entry after irradiation. ATRX-deficient cells exhibit enhanced activation of master cell cycle regulator ATM with irradiation. Mice intra-cranially implanted with ATRX-deficient GBM cells demonstrate doubling of median survival compared to the ATRX-Wild Type controls when treated with ATM inhibitor AZD0156 and radiation. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display epigenetic dysregulation of cell cycle phase transitions, which opens a new window for therapies targeting this unique phenotype.
2022-01-18 | GSE178113 | GEO
Project description:ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and isocitrate dehydrogenase (IDH)-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We find that ATRX binds the regulatory elements of cell-cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to the early release of G2/M entry after irradiation. ATRX-deficient cells exhibit enhanced activation of master cell-cycle regulator ATM with irradiation. Addition of the ATM inhibitor AZD0156 doubles median survival in mice intracranially implanted with ATRX-deficient GBM cells, which is not seen in ATRX-wild-type controls. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display Chk1-mediated dysregulation of cell-cycle phase transitions, which opens a window for therapies targeting this phenotype.
| S-EPMC8759735 | biostudies-literature
Project description:ATRX loss in glioma results in epigenetic dysregulation of cell cycle phase transition
| PRJNA737405 | ENA
Project description:ATRX loss in glioma results in epigenetic dysregulation of cell cycle phase transition [RNA-seq]
| PRJNA737409 | ENA
Project description:ATRX loss in glioma results in epigenetic dysregulation of cell cycle phase transition [scRNA-seq]
| PRJNA737410 | ENA
Project description:Recent work in human glioblastoma (GBM) has documented recurrent mutations in the histone chaperone protein ATRX. We developed an animal model of ATRX-deficient GBM and showed that loss of ATRX reduces median survival and increases genetic instability. Further, analysis of genome-wide data for human gliomas showed that ATRX mutation is associated with increased mutation rate at the single-nucleotide variant (SNV) level. In mouse tumors, ATRX deficiency impairs nonhomologous end joining and increases sensitivity to DNA-damaging agents that induce double-stranded DNA breaks. We propose that ATRX loss results in a genetically unstable tumor, which is more aggressive when left untreated but is more responsive to double-stranded DNA-damaging agents, resulting in improved overall survival.
| S-EPMC5381643 | biostudies-literature
Project description:Mutations of telomerase reverse transcriptase (TERT) and the ? thalassemia/mental retardation syndrome X-linked (ATRX) genes have been the subject of numerous studies on the classification and prognosis of glioma. However, the association between TERT and ATRX in World Health Organization (WHO) grade II to IV glioma remains unclear. The present study utilized Sanger sequencing and immunohistochemical methods to detect the expression of the TERT promoter region, ATRX mutations and proliferation marker protein Ki-67 (Ki-67) protein expression in 179 cases of glioma. The current study analyzed these variables and their association with clinicopathological characteristics to further basic research and provide a theoretical basis for the clinical diagnosis and treatment of this type of tumor (1). The results demonstrated that TERT promoter mutations were negatively associated with ATRX. Additionally, Ki-67 protein expression in TERT wild-type samples was higher compared with samples with ATRX deletion. Overall, the results demonstrated, for the first time to the best of the authors' knowledge, that TERT promoter mutations are negatively associated with ATRX expression in WHO grade II to IV gliomas. These findings provide a theoretical basis for further basic research and may improve clinical diagnosis and treatment of glioma in the future.
| S-EPMC6313213 | biostudies-literature
Project description:Free fatty acid receptor 2 (FFAR2, also named GPR43), is activated by short-chain fatty acids (SCFAs), such as butyrate, that are produced when gut bacteria ferment dietary fiber. FFAR2 has been suggested to regulate colonic inflammation, which is a major risk factor for the development of colon cancer and is also linked to epigenetic dysregulation in colon carcinogenesis. The current study assessed whether FFAR2, acting as an epigenetic regulator, protects against colon carcinogenesis. To mimic the mild inflammation that promotes human colon cancer, we treated mice with dextran sodium sulfate (DSS) overnight, which avoids excessive inflammation but induces mild inflammation that promotes colon carcinogenesis in the ApcMin/+ and the azoxymethane (AOM)-treated mice. Our results showed that FFAR2 deficiency promotes the development of colon adenoma in the ApcMin/+ /DSS mice and the progression of adenoma to adenocarcinoma in the AOM/DSS mice. FFAR2's downstream cAMP-PKA-CREB pathway was enhanced, leading to overexpression of histone deacetylases (HDACs) in the FFAR2-deficient mice. ChIP-qPCR analysis revealed differential binding of H3K27me3 and H3K4me3 histone marks onto the promoter regions of inflammation suppressors (e.g., sfrp1, dkk3, socs1), resulting in decreased expression of these genes in the FFAR2-deficient mice. Also, more neutrophils infiltrated into tumors and colon lamina propria of the FFAR2-deficient mice. Depletion of neutrophils blocked the progression of colon tumors. In addition, FFAR2 is required for butyrate to suppress HDAC expression and hypermethylation of inflammation suppressors. Therefore, our results suggest that FFAR2 is an epigenetic tumor suppressor that acts at multiple stages of colon carcinogenesis.
| S-EPMC6041131 | biostudies-literature
Project description:Mammalian cells infected with Toxoplasma gondii are characterized by a profound reprogramming of gene expression. We examined whether such transcriptional responses were linked to changes in the cell cycle of the host. Human foreskin fibroblasts (HFFs) in the G(0)/G(1) phase of the cell cycle were infected with T. gondii and FACS analysis of DNA content was performed. Cell cycle profiles revealed a promotion into the S phase followed by an arrest towards the G(2)/M boundary with infection. This response was markedly different from that of growth factor stimulation which caused cell cycle entry and completion. Transcriptional profiles of T. gondii-infected HFF showed sustained increases in transcripts associated with a G(1)/S transition and DNA synthesis coupled to an abrogation of cell cycle regulators critical in G(2)/M transition relative to growth factor stimulation. These divergent responses correlated with a distinct temporal modulation of the critical cell cycle regulator kinase ERK by infection. While the kinetics of ERK phosphorylation by EGF showed rapid and sustained activation, infected cells displayed an oscillatory pattern of activation. Our results suggest that T. gondii infection induces and maintains a 'proliferation response' in the infected cell which may fulfill critical growth requirements of the parasite during intracellular residence.
| S-EPMC2647804 | biostudies-literature