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Expression profiles in wild-type and IDH1 R132H/WT human astroglial cells [RNA-seq]

ABSTRACT: Mutations in the isocitrate dehydrogenase 1 (IDH1) gene are critical to oncogenesis. The exact mechanism by which mutant IDH1 drives cell transformation is still not fully understood, partially due to the difficulty of maintaining cells with endogenously mutated IDH1. We employed a “single base editing” technique and efficiently introduced the monoallelic point mutation of IDH1 R132H (IDH1R132H/WT) into non-neoplastic human astroglial cells. Characterization of our cellular models revealed that IDH1R132H/WT inhibited cell proliferation and promoted cell migration via mechanisms mediated by its oncometabolite 2-HG. Global gene expression and epigenetic analysis identified novel molecular targets of IDH1R132H/WT, namely the Hippo pathway effector, Yes-associated protein (YAP), and its downstream signaling pathway Notch. In summary, the “single base editing” strategy introduces a new paradigm that recapitulates the biological function of IDH1 R132H/WT and its oncometabolite 2-HG, which can be easily applied to other cell models. Our study provides a valuable model for novel discoveries of molecular mechanisms during IDH1 R132H/WT-driven pre-cancerous events.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103557 | GEO | 2018/06/01

REPOSITORIES: GEO

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DNA methylation profiles in wild-type and IDH1 R132H/WT human astroglial cells [methylation]

Project description:Mutations in the isocitrate dehydrogenase 1 (IDH1) gene are critical to oncogenesis. The exact mechanism by which mutant IDH1 drives cell transformation is still not fully understood, partially due to the difficulty of maintaining cells with endogenously mutated IDH1. We employed a “single base editing” technique and efficiently introduced the monoallelic point mutation of IDH1 R132H (IDH1R132H/WT) into non-neoplastic human astroglial cells. Characterization of our cellular models revealed that IDH1R132H/WT inhibited cell proliferation and promoted cell migration via mechanisms mediated by its oncometabolite 2-HG. Global gene expression and epigenetic analysis identified novel molecular targets of IDH1R132H/WT, namely the Hippo pathway effector, Yes-associated protein (YAP), and its downstream signaling pathway Notch. In summary, the “single base editing” strategy introduces a new paradigm that recapitulates the biological function of IDH1 R132H/WT and its oncometabolite 2-HG, which can be easily applied to other cell models. Our study provides a valuable model for novel discoveries of molecular mechanisms during IDH1 R132H/WT-driven pre-cancerous events.

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Project description:The cytosolic NADP+-dependent isocitrate dehydrogenase IDH1 is frequently mutated in human cancers. Recent studies have shown that IDH1 mutant primary glioblastomas (GBM) and acute myeloid leukemias (AML) display robust association with CpG island methylator phenotype (CIMP). Such observations bring into question whether IDH1 mutations directly contribute to the development of CIMP or if the hypermethylation phenotype precedes acquisition of IDH1 mutations. To reveal the effects of IDH1 mutations on DNA methylation and gene expression, we introduced the most frequently observed IDH1 mutation, R132H, into a human cancer cell line through gene targeting. We profiled changes in methylation at over 27,000 CpG dinucleotides spanning 14,475 unique gene regions and characterized genome-wide gene expression alterations resulting from IDH1R132H knockin. We observed consistent changes in both DNA methylation and gene expression when comparing two independent IDH1R132H knockin clones to their wild-type parent, and report hypermethylation of over 2,000 loci, the majority of which contained preexisting methylation in IDH1WT parental cells. These loci exhibit the same trend in primary TCGA glioblastoma tumors with mutant IDH1 as compared to those with wild-type IDH1 and have significant overlap with genes hypermethylated in glioma-CIMP+ tumors. Furthermore, we identify specific DNA methylation and gene expression alterations which correlate with IDH1 mutations in our cell-line model as well as primary glioblastomas, including hypermethylation and transcriptional silencing of RBP1. The presented data provide insight on epigenetic alterations induced by IDH1 mutations and support a contributory role for IDH1 mutants in regulation of DNA methylation and gene expression in human cancer cells. Comparison of IDH1 R132H and wild-type HCT116 cells as well as HOG cells overexpressing either wild-type IDH1 or IDH1 R132H

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Differential gene expression in IDH1-R132H Tumor Neurospheres generated from a mouse model of Low Grade Glioma

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Differential gene expression in IDH1-R132H Low Grade Glioma animal brain tumors brain in response to 10 Gy of radiation

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