长链非编码 RNA (lncRNA) 在恶性细胞转化中的作用仍然难以捉摸。我们之前发现了一种增强子相关的lncRNA，LINC01116（名为HOXDeRNA），作为将人星形胶质细胞转化为神经胶质瘤样细胞的转化因子。我们结合使用 CRISPR 编辑、RNA 纯化染色质分离和测序 (ChIRP-seq)、RNA-基因组相互作用原位作图 (iMARGI)、染色质免疫沉淀测序 (ChIP-seq)、HiC 和 RNA/DNA FISH发现 HOXDeRNA 直接与分布在整个基因组中的 35 个神经胶质瘤特异性转录因子 (TF) 启动子内的 CpG 岛结合，包括关键干细胞 TF SOX2、OLIG2、POU3F2 和 ASCL1，将它们从 PRC2 抑制中解放出来。该过程需要独特的 RNA 四链体结构和 HOXDeRNA 的其他片段，分别与 EZH2 和 CpG 相互作用。随后的转化激活多个癌基因（例如 EGFR、miR-21 和 WEE1），由 SOX2 和 OLIG2 依赖性神经胶质瘤特异性超级增强子驱动。这些结果有助于重建星形胶质细胞转化过程中的事件序列，突出了 HOXDeRNA 的中心全基因组活性，并表明在异质性和多因素神经胶质瘤发生中存在共享的 RNA 依赖性机制。版权所有 © 2024 Elsevier Inc. 保留所有权利。

The role of long non-coding RNAs (lncRNAs) in malignant cell transformation remains elusive. We previously identified an enhancer-associated lncRNA, LINC01116 (named HOXDeRNA), as a transformative factor converting human astrocytes into glioma-like cells. Employing a combination of CRISPR editing, chromatin isolation by RNA purification coupled with sequencing (ChIRP-seq), in situ mapping RNA-genome interactions (iMARGI), chromatin immunoprecipitation sequencing (ChIP-seq), HiC, and RNA/DNA FISH, we found that HOXDeRNA directly binds to CpG islands within the promoters of 35 glioma-specific transcription factors (TFs) distributed throughout the genome, including key stem cell TFs SOX2, OLIG2, POU3F2, and ASCL1, liberating them from PRC2 repression. This process requires a distinct RNA quadruplex structure and other segments of HOXDeRNA, interacting with EZH2 and CpGs, respectively. Subsequent transformation activates multiple oncogenes (e.g., EGFR, miR-21, and WEE1), driven by the SOX2- and OLIG2-dependent glioma-specific super enhancers. These results help reconstruct the sequence of events underlying the process of astrocyte transformation, highlighting HOXDeRNA's central genome-wide activity and suggesting a shared RNA-dependent mechanism in otherwise heterogeneous and multifactorial gliomagenesis.Copyright © 2024 Elsevier Inc. All rights reserved.