Epigenetic deregulation of KMT5B in glioblastoma
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ABSTRACT:
PROVIDER: PRJEB39613 | ENA |
REPOSITORIES: ENA
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Project description:Despite similarities between tumor initiating cells with stem-like properties (TICs) and normal neural stem cells, we hypothesized that there may be differences in their differentiation potentials. We now demonstrate that both bone morphogenetic protein (BMP)-mediated and ciliary neurotrophic factor (CNTF)-mediated Jak/STAT-dependent astroglial differentiation is impaired due to EZH2-dependent epigenetic silencing of BMP receptor 1B (BMPR1B) in a subset of glioblastoma TICs. Forced expression of BMPR1B either by transgene expression or demethylation of the promoter restores their differentiation capabilities and induces loss of their tumorigenicity. We propose that deregulation of the BMP developmental pathway in a subset of glioblastoma TICs contributes to their tumorigenicity both by desensitizing TICs to normal differentiation cues, and by converting otherwise cytostatic signals to pro-proliferative signals. Keywords: Genomic alterations
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Project description:Glioblastomas are the most common malignant brain tumours in adults; they are highly aggressive, heterogeneous and plastic. We have identified METTL7B as an essential regulator of lineage specification in glioblastoma, with impact on both tumour size and invasiveness in in vivo models. Single cell transcriptomic analysis of these tumours and of cerebral organoids derived from expanded potential stem cells overexpressing METTL7B identified a regulatory role for the gene in the neural stem cells to astrocyte differentiation trajectory. Mechanistically, METTL7B downregulates the expression of key neuronal differentiation players, including SALL2, via DNA methylation and post-translational modifications of histone marks.
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Project description:Glioblastomas are the most common malignant brain tumours in adults; they are highly aggressive, heterogeneous and plastic. We have identified METTL7B as an essential regulator of lineage specification in glioblastoma, with impact on both tumour size and invasiveness in in vivo models. Single cell transcriptomic analysis of these tumours and of cerebral organoids derived from expanded potential stem cells overexpressing METTL7B identified a regulatory role for the gene in the neural stem cells to astrocyte differentiation trajectory. Mechanistically, METTL7B downregulates the expression of key neuronal differentiation players, including SALL2, via DNA methylation and post-translational modifications of histone marks.
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