HOXDeRNA激活癌变转录程序与超级增强子，通过全基因组结合实现

HOXDeRNA activates a cancerous transcription program and super enhancers via genome-wide binding

MOLECULAR CELL

影响因子:16.6

分区:生物学1区 Top / 生化与分子生物学1区细胞生物学1区

发表日期:2024 Oct 17

作者: Evgeny Deforzh, Prakash Kharel, Yanhong Zhang, Anton Karelin, Abdellatif El Khayari, Pavel Ivanov, Anna M Krichevsky

DOI: 10.1016/j.molcel.2024.09.018

摘要

长非编码RNA（lncRNA）在恶性细胞转化中的作用尚未完全明了。我们之前发现一种与增强子相关的lncRNA，命名为HOXDeRNA（LINC01116），具有转化因子作用，能够将人类星形胶质细胞转变为胶质瘤样细胞。通过CRISPR编辑、RNA纯化结合测序（ChIRP-seq）、原位RNA-基因组相互作用映射（iMARGI）、染色质免疫沉淀测序（ChIP-seq）、HiC及RNA/DNA荧光原位杂交（FISH）等技术，我们发现HOXDeRNA直接结合在全基因组范围内35个胶质瘤特异性转录因子的CpG岛上，包括关键的干细胞转录因子SOX2、OLIG2、POU3F2和ASCL1，将它们从PRC2抑制中解放出来。此过程依赖于HOXDeRNA的独特RNA四重结构及其他片段，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），由依赖于SOX2和OLIG2的胶质瘤特异性超级增强子驱动。这些结果帮助重建星形胶质细胞转化的事件序列，突显HOXDeRNA在全基因组范围内的中心作用，暗示在异质且多因素的胶质瘤发生机制中存在共同的RNA依赖性机制。

Abstract

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.