Large-Scale Atlas of Mutant IDH1-Dependent Chromatin State Reprogramming, Reversibility, and Persistence
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA339790 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR4049020_1.fastq.gz | Fastqsanger.gz | |||
| SRR4049020_2.fastq.gz | Fastqsanger.gz | |||
| SRR4049030_1.fastq.gz | Fastqsanger.gz | |||
| SRR4049030_2.fastq.gz | Fastqsanger.gz | |||
| SRR4049040_1.fastq.gz | Fastqsanger.gz |
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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.
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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.
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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.
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Project description:Mutations in IDH1 and IDH2 (encoding isocitrate dehydrogenase 1 and 2) drive the development of gliomas and other human malignancies. Mutant IDH1 induces epigenetic changes that promote tumorigenesis, but the scale and reversibility of these changes are unknown. Here, using human astrocyte and glioma tumorsphere systems, we generate a large-scale atlas of mutant-IDH1-induced epigenomic reprogramming. We characterize the reversibility of the alterations in DNA methylation, the histone landscape, and transcriptional reprogramming that occur following IDH1 mutation. We discover genome-wide coordinate changes in the localization and intensity of multiple histone marks and chromatin states. Mutant IDH1 establishes a CD24+ population with a proliferative advantage and stem-like transcriptional features. Strikingly, prolonged exposure to mutant IDH1 results in irreversible genomic and epigenetic alterations. Together, these observations provide unprecedented high-resolution molecular portraits of mutant-IDH1-dependent epigenomic reprogramming. These findings have substantial implications for understanding of mutant IDH function and for optimizing therapeutic approaches to targeting IDH-mutant tumors.
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