Long noncoding RNAs: functional surprises from the RNA world

Abstract

Most of the eukaryotic genome is transcribed, yielding a complex network of transcripts that includes tens of thousands of long noncoding RNAs with little or no protein-coding capacity. Although the vast majority of long noncoding RNAs have yet to be characterized thoroughly, many of these transcripts are unlikely to represent transcriptional "noise" as a significant number have been shown to exhibit cell type-specific expression, localization to subcellular compartments, and association with human diseases. Here, we highlight recent efforts that have identified a myriad of molecular functions for long noncoding RNAs. In some cases, it appears that simply the act of noncoding RNA transcription is sufficient to positively or negatively affect the expression of nearby genes. However, in many cases, the long noncoding RNAs themselves serve key regulatory roles that were assumed previously to be reserved for proteins, such as regulating the activity or localization of proteins and serving as organizational frameworks of subcellular structures. In addition, many long noncoding RNAs are processed to yield small RNAs or, conversely, modulate how other RNAs are processed. It is thus becoming increasingly clear that long noncoding RNAs can function via numerous paradigms and are key regulatory molecules in the cell.

Figure 1.

Paradigms for how long ncRNAs function. Recent studies have identified a variety of regulatory paradigms for how long ncRNAs function, many of which are highlighted here. Transcription from an upstream noncoding promoter (orange) can negatively (1) or positively (2) affect expression of the downstream gene (blue) by inhibiting RNA polymerase II recruitment or inducing chromatin remodeling, respectively. (3) An antisense transcript (purple) is able to hybridize to the overlapping sense transcript (blue) and block recognition of the splice sites by the spliceosome, thus resulting in an alternatively spliced transcript. (4) Alternatively, hybridization of the sense and antisense transcripts can allow Dicer to generate endogenous siRNAs. By binding to specific protein partners, a noncoding transcript (green) can modulate the activity of the protein (5), serve as a structural component that allows a larger RNA–protein complex to form (6), or alter where the protein localizes in the cell (7). (8) Long ncRNAs (pink) can be processed to yield small RNAs, such as miRNAs, piRNAs, and other less well-characterized classes of small transcripts.

Figure 2.

Long ncRNAs are processed to yield small RNAs. (A) Many long processed transcripts can be post-transcriptionally cleaved to generate small RNAs (Fejes-Toth et al. 2009). A cap structure (denoted by a red star) is then added to the 5′ ends of many of these small RNAs. In addition, capped small RNAs, known as PASRs, map near the transcription start site (TSS) of many genes. (B) The nascent MALAT1 transcript is processed to yield two ncRNAs that localize to different subcellular compartments. Cleavage by RNase P simultaneously generates the 3′ end of the mature MALAT1 transcript and the 5′ end of mascRNA (Wilusz et al. 2008).

Figure 3.

MEN ɛ/β ncRNAs are essential for the structural integrity of paraspeckles. The MEN ɛ/β ncRNAs localize to paraspeckles in HeLa cells as shown by the colocalization of an RNA FISH probe with PSPC1, a known protein component of paraspeckles, fused to EYFP. Upon treating the cells with an antisense oligonucleotide (ASO) complementary to MEN ɛ/β to deplete expression of the ncRNAs, paraspeckles are disrupted. In contrast, a control ASO has no effect on paraspeckle integrity. Bar, 10 μm.