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Mol Ther. 2019 Aug 9. pii: S1525-0016(19)30359-4. doi: 10.1016/j.ymthe.2019.07.020. [Epub ahead of print]

A Cohesin-Mediated Intrachromosomal Loop Drives Oncogenic ROR lncRNA to Accelerate Tumorigenesis.

Author information

1
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.
2
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. Electronic address: renbingjia@sjtu.edu.cn.
3
Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai, P.R. China. Electronic address: zhanghe@tongji.edu.cn.
4
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. Electronic address: fanxq@sjtu.edu.cn.

Abstract

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.

KEYWORDS:

ROR lncRNA; SMC1; intrachromosomal looping; tumorigenesis

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