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We identified a specific enhancer-associated LINC01116 (named HOXDeRNA), which targeted activation transformed human astrocytes into glioma-like cells. Using a combination of RNA-Seq, ChIRP-Seq, and ChIP-Seq, we defined the transcriptomic and epigenetic changes underlying the transformation. We demonstrate that HOXDeRNA binds in trans to the promoters of 44 glioma-specific transcription factors distributed throughout the genome and derepresses them by removing the Polycomb 2 complex. This process is mediated by the RNA G-quadruplex structure of HOXDeRNA. Moreover, HOXDeRNA-induced astrocyte transformation is accompanied by the activation of glioma-specific super-enhancers enriched for binding sites of glioma master transcription factors SOX2 and OLIG2, and multiple oncogenes such as EGFR, PDGFR, BRAF, and miR-21. Our results help reconstruct the sequence of events underlying the process of astrocyte transformation and suggest a driving role of HOXDeRNA eRNA in gliomagenesis. Overall design: We investigated the epigenetic status of HOXDeRNA-occupied genes in control or HOXDeRNA-active astrocytes, using H3K27Ac (#4353, Cell Signaling) as the mark of active chromatin state, and H3K27Me3 (#9733, Cell Signaling) and EZH2 (Cat. 39002, Active Motif) as the marks associated with repressed chromatin.ENAfalseGenome-wide activation of a glioma cancerous transcription program and super-enhancers by a single enhancer HOXDeRNA [ChIP-seq]Genome-wide activation of a glioma cancerous transcription program and super-enhancers by a single enhancer HOXDeRNA [ChIP-seq]2025-09-242023-04-05PRJNA947107GSE227803960637425921