EPCO-06. THE EPIGENETIC CIRCUIT OF HOXDERNA LONG NON-CODING RNA (LNCRNA) ACTIVATES GLIOBLASTOMA-SPECIFIC TRANSCRIPTION PROGRAMS AND SUPER-ENHANCERS GENOME-WIDE, SHAPING GLIAL CELL FATE AND TRANSFORMATION

Abstract

Abstract The origin and genesis of highly malignant and heterogeneous glioblastoma remain unknown. We have recently reported a unique enhancer-associated lncRNA (eRNA) LINC01116 (named here HOXDeRNA) that is silent in the normal brain but is commonly activated during gliomagenesis and controls gene expression in miR-10b/HOXD locus in cis by reshaping the locus topology. CRISPR activation experiments suggested that HOXDeRNA is sufficient to transform human astrocytes into glioma-like cells. Conversely, the knock-down of this lncRNA strongly impacts glioma viability. We now describe the global, genome-wide regulatory role of HOXDeRNA. Once expressed in normal cells of astroglial lineage, HOXDeRNA binds to histone methyltransferase EZH2 and removes Polycomb repression from hundreds of genes encoding glioma-specific transcription factors and other essential oncogenes across the entire genome (in trans). Among them are the core neurodevelopmental transcription factors SOX2, OLIG2, POU3F2, and SALL2. This results in the activation of glioma transcriptional programs and downstream super-enhancers enriched for binding sites of glioma master transcription factors SOX2 and OLIG2. Moreover, HOXDeRNA-induced astrocyte transformation is accompanied by the activation of multiple oncogenes, such as EGFR, PDGFR, and BRAF. We further identified a specific structure within the HOXDeRNA that mediates its genome-wide promoter binding and gene regulatory activity as a PRC2 decoy. These results have been obtained using the combination of ChIRP-Seq, ChIP-Seq, RNA-Seq, CLIP, CRISPR activation, and base editing, and intersect our analysis of normal and cancer cells with large public datasets. Thus, we describe the first lncRNA driving a cancer-specific transcriptional program globally, altering the epigenetic landscape across all 23 chromosome pairs, and resulting in the neoplastic transformation of normal cells to glioma. Overall, the results help reconstruct the sequence of events underlying the process of astrocyte transformation and suggest new RNA-targeting approaches for glioblastoma therapies.