Olig1/2 Coordinately Control Oligodendrocyte Versus Interneuron Fate Acquisition in Normal Brain and H3.3G34R/V-mutant Gliomas

The co-opting of the developmental gliogenesis program is a hallmark characteristic of glioblastoma (GBM). The bHLH transcription factors Olig1/2 are co-expressed in tri-potential intermediate progenitors (tri-IPCs) and GBM cells, yet their functions in these cells remain largely unknown. Here, we demonstrate that Olig1/2 coordinately promote the generation of oligodendrocytes while repressing the generation of olfactory bulb interneurons in tri-IPCs and GBM. Mechanistically, Olig1/2 directly bind to multiple enhancers, such as hs687, DSG (downstream from Gsx2) and a putative enhancer to regulate the expression of Gsx2, thereby regulating the fate determination process of tri-IPCs during gliogenesis. Furthermore, we provide compelling evidence that human histone H3.3G34R/V-mutation tumors, a subtype of pediatric high-grade gliomas, originate from cortical-derived tri-IPCs. Altogether, our findings suggest that the molecular mechanism of Olig1/2 in gliogenesis and gliomagenesis are conserved, which will deepen our understanding of the gaps between normal development and tumorigenesis. Overall design: ScRNA-seq were performed on FACS sorted tdT+ cells from the P1 Olig1/2f/f;IS-reporter mice cortex which were electroporated of pCAG-Cre plasmid at E15.5.Emx1-CRE;Olig1/2f/f mice cortex were dissected out at P7 and immediately submerged in fresh ice-cold Hanks balanced salt solution. The cortex was then cut into pieces and dissociated into a single-cell suspension using a Papain Cell Dissociation Kit according to the manufacturer's instructions.