Multi-omic analysis of the glioblastoma epigenome and transcriptome informs of migratory interneuron-like developmental regulators

Abstract Recent studies have demonstrated that, despite their nomenclature, gliomas recapitulate an interneuron progenitor-like state that drives tumor progression. During human neurodevelopment, interneurons arise from the subcortical ganglionic eminences and migrate tangentially into the neocortex, settling in the cortical plate where they integrate local neurocircuitry. Analogously, malignant glioblastoma (GBM) cells migrate from the tumor core into the surrounding healthy tissue. This innate infiltrative property renders these malignant cells elusive to surgical resection, leading to tumor recurrence. To understand the regulatory networks that drive tumor infiltration from a neurodevelopmental perspective, we generated a single-nucleus Assay for Transposase-Accessible Chromatin sequencing (snATAC-seq) dataset of 41,000 nuclei from the core and infiltrative edge of surgically resected GBM specimens (n = 4). Concurrently, we sequenced 46,000 nuclei from non-pathological, postmortem samples of second- and third-trimester neocortices (n = 17). We integrated these datasets with paired single-nucleus RNA sequencing (snRNA-seq) data and identified candidate regulatory TFs that exhibit high correlation between motif enrichment and TF expression. Using single-trajectory inference and pseudo-time analyses, we identified TCF12 as a potential driver of interneuron lineage fate in developing cortical progenitors. Given its implication in projection neuron migration, we were intrigued to find that TCF12 activity is highest in GBM cells with a migratory interneuron signature, hinting at its putative role in tumor infiltration. To understand the significance of these findings, we will interrogate other genes in the TCF12 regulatory network with the ultimate goal of identifying therapeutic targets that inhibit GBM infiltration.