Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Mol Cell. 2024 Oct 17;84(20):3950-3966.e6. doi: 10.1016/j.molcel.2024.09.018. Epub 2024 Oct 8.
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.
长链非编码 RNA（lncRNA）在恶性细胞转化中的作用仍不清楚。我们之前发现了一种增强子相关的 lncRNA，LINC01116（命名为 HOXDeRNA），它是一种转化因子，可以将人类星形胶质细胞转化为类胶质瘤细胞。我们采用 CRISPR 编辑、RNA 纯化结合测序（ChIRP-seq）、原位 RNA-基因组相互作用作图（iMARGI）、染色质免疫沉淀测序（ChIP-seq）、HiC 和 RNA/DNA FISH 相结合的方法，发现 HOXDeRNA 直接结合到基因组中 35 个胶质瘤特异性转录因子（TFs）启动子内的 CpG 岛，这些 TFs 分布在整个基因组中，包括关键的干细胞 TFs SOX2、OLIG2、POU3F2 和 ASCL1，从而使它们摆脱 PRC2 的抑制。这个过程需要一个独特的 RNA 四链体结构和 HOXDeRNA 的其他片段，分别与 EZH2 和 CpGs 相互作用。随后的转化激活了多个癌基因（如 EGFR、miR-21 和 WEE1），由 SOX2 和 OLIG2 依赖性的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 在全基因组范围内的核心活性，并表明在其他异质和多因素的胶质瘤发生中存在共享的 RNA 依赖性机制。
