Single Cell Analysis of Chromatin Accessibility Reveals Genetic and Regulatory Heterogeneity in Glioblastomas

Intra-tumoral heterogeneity is a key contributor to therapeutic failure in glioblastomas, the most common form of primary adult brain cancer. To better define this heterogeneity, genome-wide chromatin accessibility and transcription profiles of clinical glioblastoma specimens were analyzed at single cell resolution. These profiles afforded resolution of intra-tumoral genetic heterogeneity and delineation of sub-populations characterized by focal DNA amplifications including extrachromosomal circular DNA (ecDNA) that harbor highly transcribed oncogenes. The maps of open chromatin helped define cellular states of distinct tumor cell populations characterized by unique regulatory landscapes. Unexpectedly, the diverse tumor cellular states share a common regulatory program involving the Nuclear Factor 1 transcription factors (NFIA and NFIB). Silencing of these genes suppressed glioblastoma growth in vitro and in vivo. These results demonstrate opportunities for glioblastoma therapeutic discovery through integration of single nuclear profiling platforms. Characterizing tumor heterogeneity in glioblastoma tumors using single nuclei ATAC-seq and RNA-seq >>>Submitter states that raw data will be submitted to dbGaP due to patient privacy concerns.<<<