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

Abstract

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.

Long noncoding RNA in genome regulation

“…The extensive sequence space available to lncRNAs provide plausible strategies for highly discriminative binding to the genome in an allele-or gene-specific fashion (reviewed in ref. 3). Possible RNA targeting schemes include the following (see Fig 1):…”

Suppression of progenitor differentiation requires the long noncoding RNA ANCR

“…A small subset of those long noncoding RNAs (lncRNAs) have been shown to be essential for a variety of biological processes, such as epigenetic control of chromatin (Rinn et al 2007;Wang et al 2011), promoter-specific gene regulation (Feng et al 2006;Martianov et al 2007), X-chromosome inactivation (Lee 2009;Tian et al 2010), imprinting (Bartolomei et al 1991;Lyle et al 2000), nuclear import (Willingham et al 2005), and maintenance of nuclear body structure (Mao et al 2011). More recently, loss-of-function studies with a large number of lncRNAs expressed in mouse embryonic stem cells showed that lncRNAs regulate gene expression patterns that control pluripotent state or lineage commitment programs in stem cells (Guttman et al 2011).…”

The activatory long non-coding RNA DBE-T reveals the epigenetic etiology of facioscapulohumeral muscular dystrophy

“…There are several examples of PRC2-recruiting lncRNAs. In mammals, Xist lncRNA coats one of the X chromosome in cis, then the RepA lncRNA recruits PRC2, interacting with Xist and spreading across the chromosome, finally resulting in histone methylation (H3K27m3) and heterochromatin formation [3] (Figure 1A). Another lncRNA, known as HOTAIR, was shown to recruit the PRC2 complex and to silence 40 kb of the HOXD locus [4].…”