Antibody blockade resets CHI3L1-induced glioma stem cell phenotypic transitions and reduces glioblastoma tumor burden

CHI3L1 (Chitinase 3-like1) is one of the highest expressed genes in glioblastoma and is associated with therapy resistance and low survival of patients. Here, we show that exposure of glioma stem cells (GSCs) to CHI3L1 induces marked phenotypic and transcriptomic change from CD133+/SOX2+ pro-neural to CD44+/CHI3L1+ mesenchymal phenotype. CHI3L1 induces chromatin remodeling in GSCs and regulates accessibility of ZNF281, CTCFL, SOX9, and the OCT4-SOX2-TCF3-NANOG transcription factor complex that drive the CHI3L1-mediated mesenchymal “switch” and maintain GSC identity. We performed ATAC-Seq on CHI3L1-treated and non-CHI3L1-treated (CTRL) glioma stem cells to determine changes in chromatin accessibility following exposure to CHI3L1. Annotation of the peaks showed that the CHI3L1-treated group has an increased proportion of its accessible regions occurring at promoters within 1000 bp of a TSS (36.86% in CHI3L1-treated vs. 32.90% in CTRL). Furthermore, the peak densities at the TSS showed increases in signal for the CHI3L1 treated group, indicating that the TSSs are comparatively more accessible. Please note that each processed data was generated from both replicates and is linked to the corresponding rep1 sample records.