A Cohesin-Mediated Intrachromosomal Loop Drives Oncogenic ROR lncRNA to Accelerate Tumorigenesis
A Cohesin-Mediated Intrachromosomal Loop Drives Oncogenic ROR lncRNA to Accelerate Tumorigenesis
复制标题
粘连蛋白介导的染色体内环驱动致癌 ROR lncRNA 加速肿瘤发生
DOI：
10.1016/j.ymthe.2019.07.020
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发表时间：
2019-12-04
影响因子：
12.4
通讯作者：
Fan, Xianqun
中科院分区：
文献类型：
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作者：
Fan, Jiayan;Xu, Yangfan;Fan, Xianqun
长非编码RNA(LncRNAs)是一类重要的广泛存在的非编码RNA，参与多种生物学功能。大量研究表明，它们在人类疾病，特别是癌症中起着重要的调节作用。然而，lncRNAs转录的机制尚未完全阐明。在这里，对ROR IncRNA位点的局部染色质结构的比较发现，一个粘附素复合体介导的染色体内环与ROR启动子的上游增强子并列，使肿瘤细胞中的内源性ROR IncRNA能够被激活。在正常对照细胞中没有观察到这种染色体的相互作用。RNAi敲除SMCI或CRISPR/Cas9删除增强子DNA可消除染色体内相互作用，导致ROR 1ncRNA沉默并抑制荷瘤动物的肿瘤进展。我们的结果揭示了一种新的机制，即粘附素协调的染色体内环可能作为关键的表观遗传驱动因素激活ROR IncRNA的转录，从而诱导肿瘤发生。我们的数据代表了IncRNA调节的一种新的染色体折叠模式，从而为IncRNA触发的肿瘤发生中的染色体相互作用提供了一个新的替代概念。
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 IncRNA locus revealed a cohesin-complex-mediated intrachromosomal loop that is juxtaposed with an upstream enhancer to the ROR promoter, enabling activation of endogenous ROR IncRNA in tumor cells. This chromosomal interaction was not observed in normal control cells. Knockdown of SMCI by RNAi or deletion of the enhancer DNA by CRISPR/Cas9 abolished the intrachromosomal interaction, resulting in ROR 1ncRNA 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 IncRNA, subsequently inducing tumorigenesis. Our data represent a novel chromosomal folding pattern of IncRNA regulation, thereby providing a novel alternative concept of chromosomal interaction in lncRNA-triggered tumorigenesis.