Changes in chromatin state reveal a central role for the transcription factor ARNT2, in the control of glioblastoma stem cell tumorigenicity

Although a growing body of evidence indicates that the phenotypic plasticity exhibited by glioblastoma cells plays a central role in tumor development and post-therapy recurrence, the master drivers of their aggressiveness remain elusive. Here we mapped the changes in the transcriptionally permissive (H3K4me3) and repressive (H3K27me3) epigenetic histone marks accompanying the repression of glioblastoma stem cells (GSC) tumorigenicity. Genes with changing marks delineated a network of transcription factors related to cancerous behavior, stem state, and neural development, which highlighted a previously unsuspected association between repression of ARNT2 and loss of cell tumorigenicity. Immunohistochemistry confirmed ARNT2 expression in cell sub-populations of patients’ glioblastoma. Its transcriptional repression was consistently found in non-tumorigenic glioblastoma cells, compared to tumorigenic cells. Moreover, ARNT2 expression correlated with a stem signature at both the tissue level within the tumor core and at the single cell level in the patients’ tumors. ARNT2 knockdown decreased expression of the transcription factors SOX9, POU3F2 and OLIG2 known promoters of glioblastoma cell tumorigenicity, and repressed GSC tumorigenic properties in vivo. Our results unveil ARNT2 as a master gene of the glioblastoma tumorigenic cell signature, located at a node of the transcription factor network controlling glioblastoma cell aggressiveness.