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Large-Scale Atlas of Mutant IDH1-Dependent Chromatin State Reprogramming, Reversibility, and Persistence [methylation]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE85938 | GEO | 2017/08/23

SECONDARY ACCESSION(S): PRJNA339797

REPOSITORIES: GEO

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Project description:Gene expression of mouse hepatoblasts (HBs) expressing IDH1 WT, IDH1 R132C, IDH2 WT, R172K and empty vector controls (N=2 cultures for each condition) grown on collagen-coated plates and IDH1 R132C and empty vector controls on uncoated plates were evaluated using Affymetrix Mouse 430Av2 DNA microarrays that were processed at the Dana-Farber Cancer Institute core facility (http://macf-web.dfci.harvard.edu/) using their standard protocol. Mutations in Isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly primary liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert alphaketoglutarate (aKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple aKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks primary liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF4a, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models (GEMMs) expressing mutant IDH in the adult liver show aberrant response to hepatic injury, characterized by HNF4a silencing, impaired hepatocyte differentiation and markedly elevated levels of cell proliferation. Moreover, mutant IDH and activated Kras, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis and present a novel GEMM of IDH-driven malignancy. Gene expression of HBs expressing IDH1 WT, IDH1 R132C, IDH2 WT, R172K and empty vector controls under a doxycycline-inducible system (N=2 cultures for each condition) grown on collagen-coated plates and IDH1 R132C and empty vector controls on uncoated plates were evaluated using Affymetrix Mouse 430Av2 DNA microarrays.

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Large-Scale Atlas of Mutant IDH1-Dependent Chromatin State Reprogramming, Reversibility, and Persistence [methylation]

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