Glioblastoma epigenome profiling identifies SOX10 as a master regulator of molecular tumour subtype - tumour ChIPseq data

Glioblastomas 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 are common during treatment, and transitions to the mesenchymal (MES) subtype are associated with therapy resistance and adverse prognosis. Here, we present DNA methylome and histone modification data of glioblastoma primary tumours and find that glioblastoma subtypes differ in their enhancer landscapes. Using Core Regulatory Circuitry analysis of chromatin and orthogonal analysis of RNA-derived gene regulatory networks, we identified 38 subtype Master Regulators whose cell population-specific activities we further mapped in single-cell RNA sequencing data. These analyses identified the oligodendrocyte precursor marker and chromatin modifier SRY-Box 10 (SOX10) as a master regulator in RTK I tumours. In vitro functional studies demonstrated that SOX10 loss causes a subtype switch analogous to the proneural-mesenchymal Transition observed in patients at the transcriptomic, epigenetic and phenotypic levels. This subtype transition is dependent on the activity of the SOX10 and enhancer co-factor Bromodomain Containing 4 (BRD4). Sox10 repression in an in vivo syngeneic graft glioblastoma mouse model results in increased tumour invasion, immune cell infiltration and significantly reduced survival, reminiscent of progressive human glioblastoma. These results identify SOX10 as a bona fide master regulator of the RTK I subtype, with both tumour cell-intrinsic and microenvironmental effects, highlighting that both glioblastoma cell plasticity and their tumour-microenvironment interactions are important contributors to tumour phenotypes. 20 GBs (IDH: 6; MES: 4; RTK I and RTK II: 5 each) were characterised by histone mark ChIPseq (H3K27ac, H3K27me3, H3K4me1, H3K4me3, H3K36me3, H3K9me3, with WGS as input control). The following analyses were performed on the above data: - ChromHMM analysis (using the Roadmap Epigenome 18-state model) - superenhancer analysis (on H3K27ac data) - active enhancer analysis (combining H3K27ac, H3K4me1 data) Please note that [1] the processed data files generated from multiple samples are linked as Series supplementary files and are indicated in the corresponding sample description field [2] Raw data requires controlled access and is deposited at EGAS00001003230.