A Transcriptional State Driven by Yin Yang 1 Confers a Therapeutic Vulnerability in Glioblastoma Stem Cells

Glioblastoma (GBM) is the most lethal primary brain cancer characterized by resistance to chemotherapy and radiotherapy, which is driven by GBM stem cells (GSCs). Here, we interrogated gene expression profiles and whole genome CRISPR/Cas9 screening in a large panel of patient-derived GSCs, differentiated glioblastoma cells (DGCs), and neural stem cells (NSCs) to identify master regulators of GSC stemness, revealing a dependency on Yin Yang 1 (YY1) in GSCs. YY1 controlled a cell state with increased RNA polymerase II-mediated transcription and RNA processing through interaction with transcriptional cyclin-dependent kinases (CDKs) and regulating chromatin loop formation in GSCs. YY1 and transcriptional CDKs were essential in GSC survival and stemness maintenance in vitro and in vivo. Moreover, YY1 knockdown or simultaneously targeting transcriptional CDKs elicited interferon responses and augmented efficacy of immune checkpoint therapy. Collectively, these results suggest that YY1-mediated chromatin regulation defines a targetable cell state with active transcription and immunotherapy resistance in glioblastoma.