Unique features of long non-coding RNA biogenesis and function

The transcriptional landscape of all organisms is far more complex than was originally imagined, as the vast majority of genomic sequence is pervasively transcribed into a diverse range of protein-coding RNAs and non-coding RNAs (ncRNAs). In this expanded view of both the genome and the transcriptome, our catalogue of genetic elements is now brimming with long non-coding RNAs (lncRNAs), a loosely classified group of long RNA transcripts with no apparent protein-coding role. lncRNAs are found in every branch of life, and organismal complexity is better correlated with the diversity and size of non-coding RNA expression repertoires than with that of protein-coding genes. lncRNAs are diverse and numerous; by most estimates, the number of human lncRNAs outstrips the number of protein-coding genes. The total number of lncRNAs continues to climb, catalysed by deeper and more sensitive RNA sequencing, improved epigenomic technologies and computational prediction techniques. Their growing ranks have motivated an increased focus on understanding the roles of lncRNAs in biology.

Cis-regulatory mechanisms of lncRNA function

a | Long non-coding RNAs (lncRNAs) are uniquely poised to regulate their genomic neighbourhoods in cis. Some enhancer RNAs, such as LUNAR1 near the insulin-like growth factor 1 receptor (IGF1R) locus, mediate chromosome looping between enhancers and nearby target genes via Mediator or MLL protein complexes. b | PcG response element/TrxG response element (PRE/TRE) enhancer RNAs can switch between silencing and activating states by switching bidirectional transcription; forward transcription of one such PRE/TRE represses vestigial expression via Polycomb group (PcG), whereas transcription in the reverse direction activates vestigial expression via Trithorax group (TrxG). c | Allele-specific DNA methylation at imprinted genomic loci silences the expression of lncRNAs within the imprinted gene cluster, thereby allowing neighbouring protein-coding genes to be expressed; conversely, on the other allele the lncRNA is expressed in the absence of DNA methylation, thereby repressing protein-coding genes in cis. d | The mammalian dosage compensation lncRNA, Xist, is silenced on the active X chromosome in cis by the antisense lncRNA Tsix; meanwhile, Xist is activated on the inactive X chromosome in cis and in trans by the lncRNA Jpx. e | ANRIL antisense lncRNA represses the cyclin-dependent kinase inhibitor 2A (CDKN2A)–CDKN2B locus in cis by recruiting PRC1 and PRC2. f | When protein-coding genes and antisense lncRNA genes overlap, processing RNA polymerase II (Pol II) particles may collide and thus abort transcription, effectively inhibiting the expression of both genes. g | FMR1 (fragile X mental retardation 1) binds and silences its own promoter via RNA–DNA hybrids at CGG repeat expansions that are characteristic of disease. h | roX1 in male Drosophila spp. autoregulates its own locus and sustains its own transcription by recruiting the activating dosage compensation complex (DCC).

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