Glioblastoma epigenome profiling identifies SOX10 as a master regulator of molecular tumour subtype - cell line Illumina v4 human beadarrays

ABSTRACT: Glioblastoma in adult patients are classified into four subtypes, IDH, MES, RTK I, and RTK II, based on DNA methylation and RNA expression data. Tumour subtype transitions commonly occur during the treatment of glioblastoma patients, and transitions to the mesenchymal (MES) subtype have been associated with therapy resistance and adverse prognosis. Here, we generate DNA methylome and histone modification data of glioblastoma primary tumours and show that glioblastoma subtypes differ by their enhancer landscapes. Using Core Regulatory Circuitry analysis of H3K27ac data, and independent analysis of RNA-derived gene regulatory networks, we identified 38 subtype master regulators whose cell type-specific activities we mapped in single-cell RNA sequencing data. These analyses identified the chromatin modifier SRY-Box 10 (SOX10) as a master regulator in tumours of the RTK I subtype. In functional studies we demonstrate that SOX10 loss causes a transition of RTK I tumour cells to a mesenchymal cellular state by altering the accessibility of enhancer-rich chromatin regions and their occupancy by Bromodomain Containing 4 (BRD4), a dynamic constituent of super-enhancers. Treatment with the BRD4 inhibitor JQ1 blocked this transition. These data demonstrate the fundamental role of enhancer chromatin remodelling and master regulator activity in the establishment, maintenance and plasticity of glioblastoma cellular states. We also make our data publically browsable at https://dkfz-b060.github.io/gb_browse/ Overall design: Two RTK I-like cell lines were transduced with experimental systems that allow repression of the SOX10 gene: LN229 with CRISPRi, and ZH487 with shRNA. In each case, 3 independent SOX10-targeting reagents were used. In this series, expression microarray profiling was used to compare the transcriptomes of the two models with and without repression of SOX10 expression and the effect of BET inhibition using JQ1. After processing, condition-specific transcriptomes were analysed using GSEA (v3.0) and the Verhaak 2010 glioblastoma subtype signatures for Proneural and Mesenchymal.

INSTRUMENT(S): Illumina HumanHT-12 V4.0 expression beadchip

ORGANISM(S): Homo Sapiens

SUBMITTER: Bernhard Radlwimmer  

PROVIDER: GSE135674 | GEO | 2019-08-11

REPOSITORIES: GEO