Structure Prediction: New Insights into Decrypting Long Noncoding RNAs

Abstract

Long noncoding RNAs (lncRNAs), which form a diverse class of RNAs, remain the least understood type of noncoding RNAs in terms of their nature and identification. Emerging evidence has revealed that a small number of newly discovered lncRNAs perform important and complex biological functions such as dosage compensation, chromatin regulation, genomic imprinting, and nuclear organization. However, understanding the wide range of functions of lncRNAs related to various processes of cellular networks remains a great experimental challenge. Structural versatility is critical for RNAs to perform various functions and provides new insights into probing the functions of lncRNAs. In recent years, the computational method of RNA structure prediction has been developed to analyze the structure of lncRNAs. This novel methodology has provided basic but indispensable information for the rapid, large-scale and in-depth research of lncRNAs. This review focuses on mainstream RNA structure prediction methods at the secondary and tertiary levels to offer an additional approach to investigating the functions of lncRNAs.

Keywords: function; lncRNAs; secondary structure; structure prediction; tertiary structure.

Figure 1

The graphical abstract of this review.

Figure 2

Mechanisms of lncRNA action in transcriptional regulation. (a) Transcription of the lncRNA SRG1 inhibits the expression of the SER3 gene by interfering with the binding of RNA polymerase II to DNA; (b) The expression of the p15 antisense RNA, the lncRNA of a tumor suppressor gene, results in the silencing of the p15 gene through the induction of heterochromatin formation, which persisted after the p15 antisense RNA was turned off; (c) lncRNA binds to the major DHFR promoter and IIB, a general transcriptional factor, to form a stable and specific complex to dissociate the preinitiation complex from the major DHFR promoter; (d) As a response to stress, the RNA-binding protein TLS, under allosteric modulation via lncRNA upstream of CCND1, binds to chromatin-binding protein (CBP) and inhibits CBP/P300 HAT activities on CCND1; (e) The lncRNA Evf2, a crucial co-enhancer of regulatory proteins involved in transcription, cooperates with the Dlx2 protein to activate the Dlx5/6 enhancer in a target gene; (f) In response to heat shock, the lncRNA HSR1 (heat shock RNA-1) promotes the trimerization of HSF1 (heat-shock transcription factor 1), and consequently the translation factor EIF interacts with HSR1 and HSF1 to forms a complex to facilitate the expression of heat-shock protein (HSP); (g) NFAT is nuclear factor of activated T cells. The lncRNA NRON (noncoding repressor of NFAT) may form a complex with importin proteins to regulate the subcellular localization of NFAT. The knockdown of NRON increases the expression and activity of NFAT; (h) The lncRNA metastasis-associated lung adenocarcinoma transcript 1(MALAT1) has been shown to be abnormally expressed in many human cancers. The nascent MALAT1 transcript is cleaved by RNase P to produce the 3′ end of the mature MALAT1 transcript and the 5′ end of the small RNA; (i) Several studies have elucidated that some lncRNAs can act as microRNA sponges to competitively bind to microRNAs and decrease microRNA-induced tumorsphere differentiation.