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.
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.
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.
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.
Project description:Investigation of whole genome gene expression level changes in a B. suis 1330 regA mutant, compared to the wild-type strain. The two-component system RegBA of Brucella suis plays a central role in the control of respiratory systems adapted to oxygen deficiency. The mutant strain is affected in long-term persistence in vitro (this study) and in chronic infection in vivo (Abdou, E et al. 2013, Infect.Immun. 81: 2053-61). Using an original “in vitro model of persistence”, we compare large-scale transcriptome of the wild-type and ∆regA strains to identify the RegA-regulon potentially involved in the set-up of the persistence state.
Project description:Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2 hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large AML patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells rapidly induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the α-ketoglutarate-dependent enzyme TET2, and TET2 loss-of function mutations associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem cell marker expression, suggesting a shared pro-leukemogenic effect. DNA methylation and gene expression profiling in IDH1/2 mutant vs. IDH1/2 wild-type AML