GSE103274
Genome-wide maps of chromatin state in CD15-positive tumor-derived glioblastoma cells [ChIP-seq]
We report that these features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile and hypoxic regions a mesenchymal pattern.  As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches.  Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein. To determine the differential regional activation of EZH2 and BMI1 function, we performed chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) with H3K27me3 (histone modification by EZH2) or H2AK119Ub (histone modification by BMI1) antibodies in CD15-postive GSCs from enhancing and necrotic regions of two GBM specimens, and found over 80% of regional specific target genes displayed distinct H3K27me3 or H2AK119Ub marks, indicating distinct PRC function in GSCs residing in different regions. H3K27me3, generally associated with inhibition of transcription, marked neuronal and cellular development targets in both the enhancing and necrotic regions, albeit without substantial overlap in gene identity, with EZH2/SUZ12/H3K27me3 targets most significantly in the enhancing regions.  In contrast, H2AK119Ub marked very different targets in the enhancing and necrotic regions, with H2AK119Ub in CD15-positive GSCs from the hypoxia (necrotic) regions marking genes strongly associated with mesenchymal subtype signaling pathways, such as TGFb, NFkB, and WNT, indicating probable microenvironment-specific functions of EZH2 and BMI1. Overall design: Examination of 2 different histone modifications in in CD15-positive GSCs from enhancing and necrotic regions of two glioblastoma specimens.