lincRNAs: genomics, evolution, and mechanisms

Abstract

Long intervening noncoding RNAs (lincRNAs) are transcribed from thousands of loci in mammalian genomes and might play widespread roles in gene regulation and other cellular processes. This Review outlines the emerging understanding of lincRNAs in vertebrate animals, with emphases on how they are being identified and current conclusions and questions regarding their genomics, evolution and mechanisms of action.

Figure 1. Assembling lincRNA Collections

(A) Data sets useful for constructing lincRNA transcript models. Information from the indicated genome-wide data sets are plotted for the CRNDE lincRNA locus (chr16:54,950,197-54,963,922 in the human hg19 assembly). A subset of ESTs from GenBank and the corresponding RefSeq annotations are also shown. ChIP-seq and CAGE (ENCODE project, HeLaS3 cells), 3P-Seq (HeLa cells, C. Jan and D.P.B., unpublished data), RNA-seq (HeLa cells; Guo et al., 2010) were plotted using the UCSC genome browser. (B) A generic lincRNA annotation pipeline, illustrating criteria used to filter potential mRNAs from the list of candidates.

Figure 2. Ribosomal Association and Subcellular Localization of lincRNAs

(A) A potential role for a lincRNA uORF. Translation of a uORF into a peptide that is rapidly degraded would prevent ribosomal scanning of downstream regions, thereby protecting downstream binding factors from displacement by scanning ribosomes. (B) Translating a nascent peptide sequence that induces ribosomal stalling would achieve an effect similar to that described in (A). (C) The uORF can recruit a ribosome, which might be important for downstream lincRNA function. (D) The translation of a uORF might influence the susceptibility of the lincRNA to different RNA decay pathways, such as nonsense-mediated decay (NMD). (E) Relative subcellular localization of mRNAs and lincRNAs in MCF-7 cells. mRNA annotations were from Ensembl, and lincRNA annotations were from Ensembl, Refseq and (Cabili et al., 2011). RPKM (reads per kilobase per million mapped reads) values were computed with Cufflinks (Trapnell et al., 2010) using RNA-seq data for nuclear and cytoplasmic fractions of MCF-7 cells (Djebali et al., 2012). Ratios for selected lincRNAs are indicated.

Figure 3. Evolution of Cyrano and Miat lincRNAs

(A) Cyrano. Gene models from the indicated species are shown, together with the PhastCons track. The gray bar indicates a ~70 nt region of homology detected in a focused search, starting with the zebrafish ortholog. (B) Miat. Gene models from the indicated species are shown, together with the PhastCons track. The gray box indicates a region in the last exon that contains multiple copies of the (U)ACUAAC(C) motif, as shown for human and frog.

Figure 4. Evolution of the Malat1 and Neat1 lincRNAs

(A) Malat1 gene models from the indicated species are shown, together with the PhastCons track indicating homology to the human genome detected in the whole-genome alignments. The gray box corresponds to the region of sequence similarity at the 3′ end of Malat1. (B) The human NEAT1/MALAT1 locus. (C) Neat1 and its similarities with Malat1. The human gene models are shown, together with annotated repeats and the PhastCons track for Neat1.

Figure 5. Diverse Mechanisms Proposed for lincRNA Function

Modes of action include cotranscriptional regulation (e.g., through either the interaction of factors with the nascent lincRNA transcript or the act of transcribing through a regulatory region), regulation of gene expression in cis or in trans through recruitment of proteins or molecular complexes to specific loci, scaffolding of nuclear or cytoplasmic complexes, titration of RNA-binding factors, and pairing with other RNAs to trigger posttranscriptional regulation. The two latter mechanisms are illustrated in the cytoplasm (where they are more frequently reported) but could also occur in the nucleus. Additional mechanisms will presumably be proposed as additional functions of lincRNAs are discovered.