ReviewThe ways of action of long non-coding RNAs in cytoplasm and nucleus
Graphical abstract
Introduction
As early as 1990, scientists found a non-coding RNA when they aimed to find new protein-coding genes involved in a particular biological function by screening the cDNA library of a fetal liver, which is different from classic non-coding RNAs such as ribosomal RNAs (rRNAs) and transfer RNAs (tRNAs) (Brannan et al., 1990, Brown et al., 1991). At that time, the main object studied was associated with genes encoding proteins and much less was known about non-coding RNAs. The number of human protein-coding genes is less than 2% of the whole genome sequence even though it has recently settled at approximately 20,000 (Ponting and Belgard, 2010, Stein, 2004). But it is now clear that up to 90% of eukaryotic genomes are transcribed, generating an extraordinary range of RNAs with no coding capacity (Costa, 2010, ENCODE Project Consortium et al., 2007). Based on transcript size, these non-coding RNAs can be grouped into two major classes: small non-coding RNAs (< 200 bp) and long non-coding RNAs (lncRNAs; ≥ 200 nt). To date, the most extensively studied small RNAs are microRNAs (miRNAs). In this review, we will mainly talk about diverse ways of action of lncRNAs in the cytoplasm and the nucleus.
LncRNAs share many features of mRNAs as they are frequently transcribed by RNA polymerase II and are generally spliced, 5′ capped, and polyadenylated. They are also marked by trimethylation of lysine4 of histone H3 (H3K4me3) at their promoter and trimethylation of lysine36 of histone H3 (H3K36me3) along the length of the transcribed region (Guttman et al., 2009, Khalil et al., 2009, Mikkelsen et al., 2007). However, not all of lncRNAs are like these. Some of them do not have polyadenosine tail (poly(A) tail) such as MALAT1 (Wilusz et al., 2012), asOct4-pseudogene 5 (Hawkins and Morris, 2010), and BC200 RNA (Chen et al., 1997, Iacoangeli et al., 2004). Compared with protein-coding genes, lncRNAs have limited coding potential as indicated by the lack of significant open reading frames (ORFs), typical initiation codon, 3-untranslated regions (UTRs) and termination codon (Ramskold et al., 2009). What is more, the expression of lncRNAs is much lower and more tissue-specificity (Mercer et al., 2008). However, in the nucleus and the cytoplasm, lncRNAs are involved in various physiological and pathological processes at epigenetic, transcriptional or post-transcriptional level to regulate the expression of related genes. So investigation of the sub-cellular distribution of lncRNAs has the potential to greatly expand our knowledge of not only the function of lncRNAs but also the guidance for newly discovered lncRNAs.
Section snippets
Classification of lncRNAs
With the development of high-throughput sequencing technology and computational methods for assembling the transcriptome, more and more lncRNAs are being constantly discovered (Cheng et al., 2005, Prensner et al., 2011). Recent observations of novel long ncRNA species have led to a complex set of terms and terminologies used to describe a given lncRNA. These include antisense lncRNAs, sense lncRNAs, intergenic lncRNAs, transcribed-ultraconserved regions (T-UCRs) and enhancer-lncRNAs (Djebali et
Function of lncRNAs
LncRNAs initially were considered as byproduct of transcription of RNA polymerase II. They had been described as “dark matter” and did not have a biological function. However, whole genome transcriptomic analyses have identified large numbers of dynamically expressed long non-coding RNAs, many of which are involved in a variety of biological functions. Increasing numbers of lncRNAs have been shown to have functional roles in body development and tumorigenesis by regulating related gene
The ways of action of lncRNAs in the cytoplasm
In the cytoplasm, lncRNAs regulate gene expression mainly at post-transcriptional level. On the one hand, lncRNAs can facilitate mRNA decay, stabilize mRNAs, and promote or inhibit the translation of target mRNAs through extended base-pairing. On the other hand, lncRNAs can also function as the precursor of microRNAs or compete for microRNA-mediated inhibition, leading to increasing expression of the mRNA (Fig. 2).
The ways of action of lncRNAs in the nucleus
In eukaryotes, various nuclear bodies as well as RNAs and proteins locate in the cell nucleus, where several nuclear processes are executed. In the nucleus, it is likely that RNAs play a vital role in the organization of nuclear domains. LncRNAs control the epigenetic state of particular genes, participate in transcriptional regulation, involve in alternative splicing and constitute subnuclear compartments (Fig. 3).
Conclusion
Compared with small RNAs and protein-coding transcripts, several thousands of putative lncRNAs have been identified in mammals, while only relatively few have been studied in any detail. In addition, as the sequence and secondary structure of lncRNAs are generally not conserved, it prohibits the de novo prediction of lncRNA domains and functions like we take for granted in protein-coding transcripts. However, there is no doubt that lncRNAs are involved in a range of developmental processes and
Acknowledgments
We acknowledge supports from the National Natural Science Foundation of China (81271203) and from the Tianjin Municipal Science and Technology Commission (12JCZDJC21600).
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