Hoxderna通过全基因组结合激活癌变转录程序和超级增强剂
HOXDeRNA activates a cancerous transcription program and super enhancers via genome-wide binding
影响因子:16.60000
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
摘要
长的非编码RNA(LNCRNA)在恶性细胞转化中的作用仍然难以捉摸。我们先前以前将增强子相关的LNCRNA LINC01116(名为Hoxderna)鉴定为将人星形胶质细胞转化为神经胶质瘤样细胞的变革性因素。 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分布在整个基因组中的转录因子(TFS),包括关键的干细胞TFS SOX2,OLIG2,POU3F2和ASCL1,使它们摆脱了PRC2抑制。这个过程分别需要与EZH2和CPG相互作用的独特的RNA四链体结构和其他片段。随后的转化激活了由Sox2-和Olig2依赖性胶质瘤特异性超级增强剂驱动的多种发病基因(例如EGFR,MiR-21和WEE1)。这些结果有助于重建星形胶质细胞转化过程的事件序列,强调Hoxderna的全基因组活性,并在异质和多因素神经胶原性中提出共享的RNA依赖机制。
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.