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. 2009 Aug 15;23(16):1831-42.
doi: 10.1101/gad.1811209.

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

Jeannie T Lee  1
Affiliations

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

Jeannie T Lee. Genes Dev. .

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.

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Figures

Figure 1.
Figure 1.
Noncoding genes of the Xic. The large noncoding elements Xist, Tsix, and Xite are now well established as regulators of XCI. More recently, shorter internal transcription units have been identified from the larger loci. These include the “sense” locus RepA and the bidirectionally transcribed locus DXPas34. The regions responsible for X-chromosome pairing, counting/choice, and spreading/silencing are shown above the map.
Figure 2.
Figure 2.
Xist RNA is expressed only from the Xi, coats that chromosome in cis, and is thought to recruit the first silencing factors to the X. The photograph shows an RNA FISH experiment performed on a metaphase chromosome spread taken from a female fibroblast cell line. Xist RNA is labeled by a rhodamine dye (red). Chromosomes are counterstained with DAPI (blue, left panel; white, right panel). Arrow indicates Xi.
Figure 3.
Figure 3.
Checkpoints of XCI regulated by noncoding genes of the Xic. See the text for detailed discussion.
Figure 4.
Figure 4.
Symmetry break mediated by homologous chromosome pairing. Adapted from Anguera et al. (2006). The two X chromosomes are epigenetically identical and euchromatic in the pre-XCI stage. The two Xs are brought together by Ctcf, Tsix, and Xite (pairing) during cell differentiation to enable cross-talk and mutually exclusive choice of Xa and Xi. Because it is thermodynamically favorable to do so, transcription factors such as Oct4 and others (red, green circles) that were previously randomly distributed between the two Tsix/Xite alleles stochastically shift to one X, which would then become future Xa. This shift results in monoallelic Tsix expression and differential chromatin modifications within the Xist region that lead to repression of Xist on Xa and up-regulation of Xist on Xi.
Figure 5.
Figure 5.
Tsix RNA as molecular switch for Xa and Xi. Adapted from Sun et al. (2006) with permission from Elsevier. Before XCI, biallelic expression of Tsix RNA enables the Tsix/Xist alleles on both Xs to remain euchromatic, as indicated by biallelic H3-K4 dimethylation and H4 acetylation. Paradoxically, the euchromatic state precludes Xist transcription. At the onset of XCI, silencing of Tsix on one X (future Xi) results in pre-emptive heterochromatin formation across the 40-kb Tsix/Xist locus, as indicated by loss of H3-K4me2 and H4 acetylation, and gain of H3-K27me3. Xist is poised and transactivated 100-fold upon cell differentiation. On the future Xa, persistent Tsix RNA expression maintains the 40-kb Tsix/Xist locus in cis in a euchromatic configuration. During the establishment phase, Tsix RNA also recruits the activity of Dnmt3a to the Xist promoter to methylate (lollipops) and lock in the silent state of Xist. Dnmt3a methylation is hypothetically mediated by small RNAs created from long Xist:Tsix dsRNA via the RNAi pathway in a manner similar to RDDM and TGS in yeast and plants. This idea remains to be tested.
Figure 6.
Figure 6.
The initiation of XCI controlled by interaction of Tsix, RepA, and Xist RNAs with PRC2. See the text in the figure for detailed discussion. Adapted from Zhao et al. (2008).
Figure 7.
Figure 7.
Locus- and allele-specific recruitment of protein factors by long ncRNA. RepA recruitment of PRC2 is shown as an example of how sequence-specific long ncRNAs act as tethers to chromatin to restrict recruitment exclusively in cis. See ithe text in the figure for discussion.
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References

    1. Anguera MC, Sun BK, Xu N, Lee JT. X-chromosome kiss and tell: How the Xs go their separate ways. Cold Spring Harb Symp Quant Biol. 2006;71:429–437. - PubMed
    1. Avner P, Heard E. X-chromosome inactivation: Counting, choice and initiation. Nat Rev Genet. 2001;2:59–67. - PubMed
    1. Bacher CP, Guggiari M, Brors B, Augui S, Clerc P, Avner P, Eils R, Heard E. Transient colocalization of X-inactivation centres accompanies the initiation of X inactivation. Nat Cell Biol. 2006;8:293–299. - PubMed
    1. Bell AC, West AG, Felsenfeld G. The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell. 1999;98:387–396. - PubMed
    1. Bernstein E, Allis CD. RNA meets chromatin. Genes & Dev. 2005;19:1635–1655. - PubMed

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