Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
Mol Ther. 2019 Dec 4;27(12):2182-2194. doi: 10.1016/j.ymthe.2019.07.020. Epub 2019 Aug 9.
Long noncoding RNAs (lncRNAs) are an important class of pervasive noncoding RNA involved in a variety of biological functions. Numerous studies have demonstrated their important regulatory role in human disease, especially cancer. However, the mechanism underlying the transcription of lncRNAs is not fully elucidated. Here, a comparison of local chromatin structure of the ROR lncRNA locus revealed a cohesin-complex-mediated intrachromosomal loop that is juxtaposed with an upstream enhancer to the ROR promoter, enabling activation of endogenous ROR lncRNA in tumor cells. This chromosomal interaction was not observed in normal control cells. Knockdown of SMC1 by RNAi or deletion of the enhancer DNA by CRISPR/Cas9 abolished the intrachromosomal interaction, resulting in ROR lncRNA silencing and inhibition of the tumor progression in animals carrying tumor xenografts. Our results reveal a novel mechanism by which the cohesin-orchestrated intrachromosomal looping may serve as a critical epigenetic driver to activate transcription of ROR lncRNA, subsequently inducing tumorigenesis. Our data represent a novel chromosomal folding pattern of lncRNA regulation, thereby providing a novel alternative concept of chromosomal interaction in lncRNA-triggered tumorigenesis.
长链非编码 RNA（lncRNAs）是一类广泛存在的非编码 RNA，参与多种生物学功能。大量研究表明它们在人类疾病，特别是癌症中具有重要的调节作用。然而，lncRNAs 转录的机制尚未完全阐明。在这里，对 ROR lncRNA 基因座局部染色质结构的比较揭示了一个由黏合蛋白复合物介导的染色体内环，该环与 ROR 启动子的上游增强子并列，从而使肿瘤细胞中内源性 ROR lncRNA 被激活。在正常对照细胞中没有观察到这种染色质相互作用。通过 RNAi 敲低 SMC1 或通过 CRISPR/Cas9 缺失增强子 DNA，消除了染色体内相互作用，导致 ROR lncRNA 沉默，并抑制了携带肿瘤异种移植的动物中的肿瘤进展。我们的结果揭示了一种新的机制，即黏合蛋白协调的染色体内环可能作为一种关键的表观遗传驱动因素，激活 ROR lncRNA 的转录，进而诱导肿瘤发生。我们的数据代表了 lncRNA 调节的一种新的染色体折叠模式，从而为 lncRNA 触发的肿瘤发生中的染色体相互作用提供了一种新的替代概念。
