Mammalian genome is pervasively transcribed into many different complex families of RNA. However, less than 2% of mammalian genome is transcribed into mRNA to encode proteins, whereas major portion of the genome is transcribed into interweaved and overlapping transcripts that include thousands of non-coding RNA (ncRNA) transcripts. ncRNAs more than 200 nucleotides in length are called long ncRNAs (lncRNAs), which are often transcribed by RNA polymerase II. These lncRNAs are usually devoid of open reading frames (ORFs), with or without the 3’ polyadenylation. Interestingly, expression of lncRNA is more tissue-specific than that of mRNA.
In the last several years, a large number of nuclear lncRNAs have been discovered. These lncRNAs play diverse roles in the nucleus through various mechanisms. For example, nuclear lncRNAs control the epigenetic state of particular genes, participate in transcriptional regulation, get involved in alternative splicing and constitute subnuclear compartments.
Although for most if not all of the lncRNAs, nucleus is the place of biogenesis and processing, cytoplasm is the final residence and site of action for some lncRNAs. Biogenesis of lncRNAs is quite complicated and share many features of protein-coding RNAs. Within the nucleus, they occupy the chromatin fraction. 17% of lncRNAs vs. 15% of mRNAs are enriched in the nucleus, whereas 4% vs. 26%, respectively, are enriched in the cytoplasm. Many lncRNA-mediated mechanisms of gene regulation have been identified in the cytoplasm. In the last decade or so, thousands of cytoplasmic lncRNAs have been discovered, indicating their importance for multiple cellular activities.
Known working models of cytoplasmic lncRNA function
A. lncRNAs modify mRNA stability, with 1/2-sbsRNA as an example of decreasing the stability of mRNA and BACE1-AS as an example of increasing the stability of mRNA. B. lncRNAs regulate mRNA translation, with lincRNA-p21 as an example of inhibiting the translation and AS Uchl1 as an example of promoting translation. C. lncRNAs modulate gene expression by functioning as ceRNAs, with linc-MD1 as well as CDR1as shown as examples. D. lncRNAs can give rise to microRNAs, with H19 shown as an example. E. Some lncRNAs affect protein modification, with NKILA as one of such kind of cytoplasmic lncRNAs. ORF, open reading frame; 1/2-sbsRNA, half-STAU1-binding site RNA; BACE1-AS, antisense transcript for β-secretase 1; linc-MD1, long non-coding RNA muscle differentiation 1; CDR1as, cerebellar degeneration-related protein 1 antisense transcript; NKILA, NF-κB interacting lncRNA; AS Uchl1, antisense transcript for ubiquitin carboxy terminal hydrolase L1; SINE, short interspersed element; cdc6, cell division cycle 6.