During development, master regulatory transcription factors and their transcriptional programs drive the hierarchical organization of stem and progenitor cells and their differentiated progeny. Some cancer types also rely on similar cellular hierarchies. Suvà et al. now characterize the transcriptional networks that govern the hierarchical cellular organization of glioblastoma (Cell 157, 580–594; 2014).

The authors cultured distinct populations of tumour-propagating cells (TPCs) and differentiated glioblastoma cells (DGCs) from patient-derived glioblastoma cells. Combining epigenetic mapping of active gene promoters with computational identification of transcription factor binding sites and gene expression profiles, they identified 19 transcription factors that were enriched in TPCs. Ectopic expression of these factors, alone or in combination, demonstrated that combined induction of POU3F2, SOX2, SALL2 and OLIG2 provided DGCs with tumour-propagating capacity in vitro and in vivo, and reprogrammed their epigenetic state to resemble that of TPCs. These four transcription factors were expressed in a subset of primary human glioblastomas and were essential for the tumour-propagating abilities of TPCs in vitro and in vivo in mice. Chromatin immunoprecipitation and gene expression data allowed the reconstruction of the gene networks regulated by these transcription factors, and identified the RCOR2 co-repressor as a critical factor downstream of OLIG2 that could replace OLIG2 in the reprogramming cocktail.

These analyses provide important insights into the transcriptional and epigenetic determinants that control the tumour-propagating potential of glioblastoma cells.