High-dimensional analysis reveals increased chromatin heterogeneity and reduced histone acetylation driven by mutant-IDH1 [MARS-seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE238105 | GEO | 2024/12/13
REPOSITORIES: GEO
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Project description:Malignant gliomas are heterogeneous tumors arising in the central nervous system (CNS) driven by epigenetic and metabolic aberrations. Mutations in Isocitrate DeHydrogenase (IDH1/2) enzymes, highly frequent in adult gliomas, confer a gain-of-function activity that favors the conversion of a-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), a competitive inhibitor of α-KG-dependent enzymes. These include DNA and histone lysine demethylases, resulting in an aberrant hypermethylation phenotype in mutant-IDH-expressing cells. Leveraging epigenetic-focused cytometry by time-of-flight (CyTOF) analysis, we profiled the effect of mutant-IDH1 expression on a broad panel of histone modifications. This analysis revealed extensive remodeling of chromatin patterns by mutant-IDH, with a global reduction in histone acetylation being the most prominent alteration. The loss of histone acetylation occurs rapidly following mutant-IDH1 induction and affects acetylation patterns over enhancers and intergenic regions. Furthermore, cells expressing mutant-IDH1 showed higher epigenetic heterogeneity, which may support the tumorigenic potential of these cells. Our study underscores the tight interaction between chromatin and metabolism dysregulation in glioma, highlighting novel epigenetic pathways affected by mutant-IDH1-driven metabolic rewiring.
2024-12-13 | GSE238104 | GEO
Project description:Malignant gliomas are heterogeneous tumors arising in the central nervous system (CNS) driven by epigenetic and metabolic aberrations. Mutations in Isocitrate DeHydrogenase (IDH1/2) enzymes, highly frequent in adult gliomas, confer a gain-of-function activity that favors the conversion of a-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), a competitive inhibitor of α-KG-dependent enzymes. These include DNA and histone lysine demethylases, resulting in an aberrant hypermethylation phenotype in mutant-IDH-expressing cells. Leveraging epigenetic-focused cytometry by time-of-flight (CyTOF) analysis, we profiled the effect of mutant-IDH1 expression on a broad panel of histone modifications. This analysis revealed extensive remodeling of chromatin patterns by mutant-IDH, with a global reduction in histone acetylation being the most prominent alteration. The loss of histone acetylation occurs rapidly following mutant-IDH1 induction and affects acetylation patterns over enhancers and intergenic regions. Furthermore, cells expressing mutant-IDH1 showed higher epigenetic heterogeneity, which may support the tumorigenic potential of these cells. Our study underscores the tight interaction between chromatin and metabolism dysregulation in glioma, highlighting novel epigenetic pathways affected by mutant-IDH1-driven metabolic rewiring.
2024-12-13 | GSE276663 | GEO
Project description:Gain-of-function IDH mutations define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylase enzymes, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes are critical for the dynamic regulation of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), though the functional significance of this altered epigenetic state remains unclear. Here we show that IDH1 mutant gliomas exhibit hyper-methylation at CTCF binding sites, leading to reduced binding of this methylation-sensitive insulator protein. Loss of CTCF binding is associated with a loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with demethylating agent partially restores insulator function and reduces PDGFRA expression. Conversely, CRISPR-mediated disruption of the CTCF binding sequence in IDH wildtype gliomaspheres induces PDGFRA expression and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression. CTCF occupancy characterization and histone H3K27 acetylation profiling in IDH1 mutant and wild-type glioma patient specimens and culture models. ChIP-seq raw data is to be made available through dbGaP (controlled access) due to patient privacy concerns.
2015-12-23 | E-GEOD-70991 | biostudies-arrayexpress
Project description:Mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) define glioma subtypes and are 38 considered primary events in gliomagenesis, impacting tumor epigenetics and metabolism. 39 IDH enzymes are crucial for the generation of reducing potential, yet the impact of the mutation 40 on the cellular antioxidant system is not understood. Here, we investigate how glutathione 41 (GSH) levels are maintained in IDH1 mutant gliomas, despite an altered NADPH/NADP 42 balance. We find that IDH1 mutant astrocytomas specifically upregulate cystathionine γ-lyase 43 (CSE), the enzyme responsible for cysteine production upstream of GSH biosynthesis. Genetic 44 and chemical interference with CSE in patient-derived glioma cells carrying the endogenous 45 IDH1 mutation, sensitized tumor cells to cysteine depletion, an effect not observed in IDH1 46 wild-type gliomas. This correlated with reduced GSH synthesis as shown by in vitro and in vivo 47 serine tracing and led to delayed tumor growth in mice. Thus we show that IDH1 mutant 48 astrocytic gliomas critically rely on NADPH-independent de novo GSH synthesis to maintain 49 the antioxidant defense, which uncovers a novel metabolic vulnerability in this dismal disease.
2021-11-25 | PXD022752 | Pride
Project description:Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations drive the development of gliomas and other human malignancies. Significant efforts are already underway to attempt to target mutant IDH in clinical trials. However, how mutation of IDH leads to tumorigenesis is poorly understood. Mutant IDH1 promotes epigenetic changes that promote tumorigenesis but the scale of these changes throughout the epigenome and the reversibility of these changes are unknown. Here, using both human astrocyte and glioma tumorsphere systems, we generate a large-scale atlas of mutant IDH1-induced epigenomic reprogramming. We characterize the changes in the histone code landscape, DNA methylome, chromatin state, and transcriptional reprogramming that occur following IDH1 mutation and characterize the kinetics and reversibility of these alterations over time. We discover coordinate changes in the localization and intensity of multiple histone marks and chromatin states throughout the genome. These alterations result in systematic chromatin states changes, which result in widespread gene expression changes involving oncogenic pathways. Specifically, mutant IDH1 drives alterations in differentiation state and establishes a CD24+ population that features enhanced self-renewal and other stem-like properties. Strikingly, prolonged exposure to mutant IDH1 results in irreversible genomic and epigenetic alterations. Together, these observations provide unprecedented molecular portraits of mutant IDH1-dependent epigenomic reprogramming at high resolution. These findings have significant implications for our understanding the mechanisms underlying mutant IDH function and for optimizing therapeutic approaches to targeting IDH mutant tumors.
2017-08-23 | GSE85940 | GEO
Project description:Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations drive the development of gliomas and other human malignancies. Significant efforts are already underway to attempt to target mutant IDH in clinical trials. However, how mutation of IDH leads to tumorigenesis is poorly understood. Mutant IDH1 promotes epigenetic changes that promote tumorigenesis but the scale of these changes throughout the epigenome and the reversibility of these changes are unknown. Here, using both human astrocyte and glioma tumorsphere systems, we generate a large-scale atlas of mutant IDH1-induced epigenomic reprogramming. We characterize the changes in the histone code landscape, DNA methylome, chromatin state, and transcriptional reprogramming that occur following IDH1 mutation and characterize the kinetics and reversibility of these alterations over time. We discover coordinate changes in the localization and intensity of multiple histone marks and chromatin states throughout the genome. These alterations result in systematic chromatin states changes, which result in widespread gene expression changes involving oncogenic pathways. Specifically, mutant IDH1 drives alterations in differentiation state and establishes a CD24+ population that features enhanced self-renewal and other stem-like properties. Strikingly, prolonged exposure to mutant IDH1 results in irreversible genomic and epigenetic alterations. Together, these observations provide unprecedented molecular portraits of mutant IDH1-dependent epigenomic reprogramming at high resolution. These findings have significant implications for our understanding the mechanisms underlying mutant IDH function and for optimizing therapeutic approaches to targeting IDH mutant tumors.
2017-08-23 | GSE85939 | GEO
Project description:Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations drive the development of gliomas and other human malignancies. Significant efforts are already underway to attempt to target mutant IDH in clinical trials. However, how mutation of IDH leads to tumorigenesis is poorly understood. Mutant IDH1 promotes epigenetic changes that promote tumorigenesis but the scale of these changes throughout the epigenome and the reversibility of these changes are unknown. Here, using both human astrocyte and glioma tumorsphere systems, we generate a large-scale atlas of mutant IDH1-induced epigenomic reprogramming. We characterize the changes in the histone code landscape, DNA methylome, chromatin state, and transcriptional reprogramming that occur following IDH1 mutation and characterize the kinetics and reversibility of these alterations over time. We discover coordinate changes in the localization and intensity of multiple histone marks and chromatin states throughout the genome. These alterations result in systematic chromatin states changes, which result in widespread gene expression changes involving oncogenic pathways. Specifically, mutant IDH1 drives alterations in differentiation state and establishes a CD24+ population that features enhanced self-renewal and other stem-like properties. Strikingly, prolonged exposure to mutant IDH1 results in irreversible genomic and epigenetic alterations. Together, these observations provide unprecedented molecular portraits of mutant IDH1-dependent epigenomic reprogramming at high resolution. These findings have significant implications for our understanding the mechanisms underlying mutant IDH function and for optimizing therapeutic approaches to targeting IDH mutant tumors.
2017-08-23 | GSE85938 | GEO
Project description:Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations drive the development of gliomas and other human malignancies. Significant efforts are already underway to attempt to target mutant IDH in clinical trials. However, how mutation of IDH leads to tumorigenesis is poorly understood. Mutant IDH1 promotes epigenetic changes that promote tumorigenesis but the scale of these changes throughout the epigenome and the reversibility of these changes are unknown. Here, using both human astrocyte and glioma tumorsphere systems, we generate a large-scale atlas of mutant IDH1-induced epigenomic reprogramming. We characterize the changes in the histone code landscape, DNA methylome, chromatin state, and transcriptional reprogramming that occur following IDH1 mutation and characterize the kinetics and reversibility of these alterations over time. We discover coordinate changes in the localization and intensity of multiple histone marks and chromatin states throughout the genome. These alterations result in systematic chromatin states changes, which result in widespread gene expression changes involving oncogenic pathways. Specifically, mutant IDH1 drives alterations in differentiation state and establishes a CD24+ population that features enhanced self-renewal and other stem-like properties. Strikingly, prolonged exposure to mutant IDH1 results in irreversible genomic and epigenetic alterations. Together, these observations provide unprecedented molecular portraits of mutant IDH1-dependent epigenomic reprogramming at high resolution. These findings have significant implications for our understanding the mechanisms underlying mutant IDH function and for optimizing therapeutic approaches to targeting IDH mutant tumors.
2017-08-23 | GSE85941 | GEO
Project description:Gain-of-function IDH mutations define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylase enzymes, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes are critical for the dynamic regulation of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), though the functional significance of this altered epigenetic state remains unclear. Here we show that IDH1 mutant gliomas exhibit hyper-methylation at CTCF binding sites, leading to reduced binding of this methylation-sensitive insulator protein. Loss of CTCF binding is associated with a loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with demethylating agent partially restores insulator function and reduces PDGFRA expression. Conversely, CRISPR-mediated disruption of the CTCF binding sequence in IDH wildtype gliomaspheres induces PDGFRA expression and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.
2015-12-23 | GSE70991 | GEO
Project description:Mutations in IDH1 and IDH2 genes are very common in low grade gliomas and secondary GBM. They induce hypermethylation of DNA and histones in tumor cells, and generate a specific epigenetic phenotype. Therefore, we decided to perform a chemical screen consisting of inhibitors of epigenetic regulators on patient-derived IDH mutant cell lines. Dual combinations of hit inhibitors in low doses were also analyzed to increase treatment efficiency. Individual and combinatorial effects of these inhibitors were also analyzed in wild type and IDH mutant pair of A172 GBM cell line that was derived by ectopic overexpression of mutant IDH1. GSK-J4 and Belinostat combination was highly effective on both patient-derived and engineered IDH mutant cells compared to wild type cells. Interestingly, sensitized IDH mutant cells were recovered via mutant IDH inhibitor, GSK864, which is thought as a candidate drug for IDH mutant glioma. On the other hand, viability of non-malignant fibroblasts were not affected from these drugs in these doses. GSK-J4 and Belinostat combination induce apoptosis which was shown by increased Caspase 3/7 activity, PARP cleavage and recovery with general caspase inhibitor (Z-VAD-FMK). Change in histone modifications such as H3K4me3, H3K9me3, H3K27me3 and H3K27ac were observed after mutant IDH overexpression and also drug treatments. RNA-seq and GSEA analysis revealed activation of unfolded protein and viral response pathways in IDH mutant cells which indicate increased cell stress. GSKJ4 and Belinostat induces cell cycle arrest and apoptosis by further increasing cell stress probably because of dramatic changes in chromatin structure.
2024-07-14 | GSE134120 | GEO