Very long intergenic non-coding (vlinc) RNAs directly regulate multiple genes in cis and trans

BMC Biology

Maxim Ri¹  Yuri Vyatkin¹  Denis Antonets²  Ye Cai³  Lu Tang³  Dongyang Xu³  DingDing Cai³  Huifen Cao³  Xueer Han³  Yue Chen³  Fang Wang³  Yao Qi³  Huifang Wang³  Philipp Kapranov³  Fan Gao³  Estelle Nicolas⁴  Xiang You⁵ 

[1] AcademGene Ltd., 6, Acad. Lavrentjev ave, 630090, Novosibirsk, Russia;AcademGene Ltd., 6, Acad. Lavrentjev ave, 630090, Novosibirsk, Russia;SRC VB “Vector” Rospotrebnadzor, 630559, Novosibirsk, Koltsovo, Russia;Institute of Genomics, School of Medicine, Huaqiao University, 668 Jimei Road, 361021, Xiamen, China;LBCMCP, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France;School of Medicine, Xiamen University, Xiang’an Southern Road, 361102, Xiamen, China;

关键词: lncRNA;    vlincRNA;    Regulatory networks;    RNA-chromatin interactions;    Single-molecule sequencing;    CRISPR/Cas13;    RNA processing;    Development;    Cell cycle;    Anti-cancer drugs;   

DOI  :  10.1186/s12915-021-01044-x

来源: Springer

【 摘 要 】

BackgroundThe majority of the human genome is transcribed in the form of long non-coding (lnc) RNAs. While these transcripts have attracted considerable interest, their molecular mechanisms of function and biological significance remain controversial. One of the main reasons behind this lies in the significant challenges posed by lncRNAs requiring the development of novel methods and concepts to unravel their functionality. Existing methods often lack cross-validation and independent confirmation by different methodologies and therefore leave significant ambiguity as to the authenticity of the outcomes. Nonetheless, despite all the caveats, it appears that lncRNAs may function, at least in part, by regulating other genes via chromatin interactions. Therefore, the function of a lncRNA could be inferred from the function of genes it regulates. In this work, we present a genome-wide functional annotation strategy for lncRNAs based on identification of their regulatory networks via the integration of three distinct types of approaches: co-expression analysis, mapping of lncRNA-chromatin interactions, and assaying molecular effects of lncRNA knockdowns obtained using an inducible and highly specific CRISPR/Cas13 system.ResultsWe applied the strategy to annotate 407 very long intergenic non-coding (vlinc) RNAs belonging to a novel widespread subclass of lncRNAs. We show that vlincRNAs indeed appear to regulate multiple genes encoding proteins predominantly involved in RNA- and development-related functions, cell cycle, and cellular adhesion via a mechanism involving proximity between vlincRNAs and their targets in the nucleus. A typical vlincRNAs can be both a positive and negative regulator and regulate multiple genes both in trans and cis. Finally, we show vlincRNAs and their regulatory networks potentially represent novel components of DNA damage response and are functionally important for the ability of cancer cells to survive genotoxic stress.ConclusionsThis study provides strong evidence for the regulatory role of the vlincRNA class of lncRNAs and a potentially important role played by these transcripts in the hidden layer of RNA-based regulation in complex biological systems.

【 授权许可】

CC BY