Noncoding RNAs and enhancers: complications of a long-distance relationship

Abstract

Spatial and temporal regulation of gene expression is achieved through instructions provided by the distal transcriptional regulatory elements known as enhancers. How enhancers transmit such information to their targets has been the subject of intense investigation. Recent advances in high throughput analysis of the mammalian transcriptome have revealed a surprising result indicating that a large number of enhancers are transcribed to noncoding RNAs. Although long noncoding RNAs were initially shown to confer epigenetic transcriptional repression, recent studies have uncovered a role for a class of such transcripts in gene-specific activation, often from distal genomic regions. In this review, we discuss recent findings on the role of long noncoding RNAs in transcriptional regulation, with an emphasis on new developments on the functional links between long noncoding RNAs and enhancers.

Figure 1

Different ways to identify long noncoding RNAs (ncRNAs). Thousands of long ncRNAs have been recently identified using various approaches. This figure summarizes the approaches used for the identification of large sets of long ncRNAs. (a) Using tiling arrays, regions that are being transcribed can be identified (intensity from detected transcripts are depicted in red). In the HOX cluster, hundreds of long ncRNAs have been identified as transcribed regions outside of protein-coding genes using tiling arrays. Among the better studied ones are HOTAIR [1] and HOTTIP [19]. (b) A large class of long ncRNAs in both mouse [2] and human [3] has been identified based on histone marks associated with active transcription. The presence of a H3K4me3 mark is indicative of the start site of an actively transcribed gene, and H3K36me3 often marks the body of the transcribed gene. These long ncRNAs have been called lincRNAs, for long intervening ncRNAs. (c) Several long ncRNAs, and shorter derivatives, are transcribed from 3′ untranslated regions (UTRs) of protein-coding genes and from around their promoters [7,24,25]. The function of these ncRNAs is unknown, but speculated to be involved in the regulation of transcription of the genes they are coexpressed with. (d) Enhancer-associated RNA (eRNA) is another class of long ncRNAs observed for thousands of enhancers in mouse [4]. Long ncRNAs are transcribed bidirectionally from the enhancer region, and speculated to have active roles in the regulation of nearby genes. (e) A class of long ncRNAs called ncRNA-a (activating ncRNA) can mediate the induction of a protein-coding gene at a distance, resembling classically defined enhancers [5]. ncRNA-a transcripts are defined from the GENCODE annotation of the human genome, as those ncRNAs residing at least 1 kb away from any known protein-coding gene.

Figure 2

Possible mechanisms of long noncoding RNA (ncRNA) functions. The mechanisms of long ncRNA regulation of gene expression are still not well understood. From recent studies, the opinion that they work in complexes with proteins is emerging [–4,19,26,40]. Summarized here is an overview of how long ncRNAs are currently speculated to function. The long ncRNA is expressed from an independent promoter and, in many cases, is spliced and polyadenylated. The structured, processed long ncRNA then associates to specific protein complexes. As both repressive and activating functions of long ncRNAs have been reported, it is likely that several different protein complexes can constitute these factors. The RNA–protein complex is then thought to target the promoter of the regulated gene, causing a conformational change and leading to altered gene expression. Alternatively, the long ncRNA–protein complex could target the nascent mRNA, making RNA–RNA hybrids and, thus, mediating immediately post-transcriptional control of gene expression.