Conserved cell-lineage controlled epigenetic regulation in human and mouse glioblastoma stem cells determines functionally distinct subgroups

There is ample support for developmental regulation of glioblastoma stem cells (GSCs). To further examine how cell lineage controls GSC function we have performed a cross-species epigenome analysis of mouse and human GSC cultures. We have analyzed and compared the chromatin-accessibility landscape of nine mouse GSC cultures of defined cell of origin and 60 patient-derived GSC cultures by assay for transposase-accessible chromatin using sequencing (ATAC-seq). This uncovered a variability of both mouse and human GSC cultures that was different from transcriptome analysis and better at predicting functional subgroups. In both species the chromatin accessibility-guided clusters were predominantly determined by distal regulatory element (DRE) regions, displayed contrasting sets of transcription factor binding motifs, and exhibited different functional and drug-response properties. Cross-species analysis of DRE regions in accessible chromatin revealed conserved epigenetic regulation of mouse and human GSCs. Human ATAC-seq data produced three distinct clusters with significant overlap to our previous mouse cell of origin-based stratification, where two of the clusters displayed significantly different patient survival. We conclude that epigenetic regulation of GSCs primarily is dictated by developmental origin which controls key GSC properties and affects therapeutic response.