Lessons from X-chromosome inactivation: long ncRNA as guides and tethers to the epigenome

Transcriptome studies are revealing that the eukaryotic genome actively transcribes a diverse repertoire of large noncoding RNAs (ncRNAs), many of which are unannotated and distinct from the small RNAs that have garnered much attention in recent years. Why are they so pervasive, and do they have a function? X-chromosome inactivation (XCI) is a classic epigenetic phenomenon associated with many large ncRNAs. Here, I provide a perspective on how XCI is achieved in mice and suggest how this knowledge can be applied to the rest of the genome. Emerging data indicate that long ncRNAs can function as guides and tethers, and may be the molecules of choice for epigenetic regulation: First, unlike proteins and small RNAs, large ncRNAs remain tethered to the site of transcription, and can therefore uniquely direct allelic regulation. Second, ncRNAs command a much larger sequence space than proteins, and can therefore achieve very precise spatiotemporal control of development. These properties imply that long noncoding transcripts may ultimately rival small RNAs and proteins in their versatility as epigenetic regulators, particularly for locus- and allele-specific control.