Identification of the Chromatin Regions Coated by Non-coding &lt;i&gt;Xist&lt;/i&gt; RNA

Murakami, Kazuhiro; Ohhira, Takahito; Oshiro, Elisa Emiko; Qi, Defeng; Oshimura, Mitsuo; Kugoh, Hiroyuki

doi:10.1159/000207514

Cited by 24 publications

(17 citation statements)

References 52 publications

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“…Our current findings of abrupt changes in chromatin modifications at transitions between genes subject to X inactivation and escape genes support our previous findings that suggest a role for the chromatin insulator protein CTCF in protecting chromatin domains (Filippova et al 2005). Depletion of H3K27me3 at escape genes is consistent with the recent findings that Xist RNA, which recruits the PRC2 complex to deposit H3K27me3 on the inactive X (Zhao et al 2008), is not present at escape genes such as Kdm5c and Kdm6a (Murakami et al 2009). Furthermore, depletion of EED, a component of the PRC2, leads to reactivation of the inactive X chromosome (Kalantry et al 2006), suggesting that H3K27me3 is important for the maintenance of the inactive X status.…”

Section: Discussionsupporting

confidence: 92%

Global survey of escape from X inactivation by RNA-sequencing in mouse

Yang¹,

Babak²,

Shendure³

et al. 2010

Genome Res.

320

400

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X inactivation equalizes the dosage of gene expression between the sexes, but some genes escape silencing and are thus expressed from both alleles in females. To survey X inactivation and escape in mouse, we performed RNA sequencing in Mus musculus × Mus spretus cells with complete skewing of X inactivation, relying on expression of single nucleotide polymorphisms to discriminate allelic origin. Thirteen of 393 (3.3%) mouse genes had significant expression from the inactive X, including eight novel escape genes. We estimate that mice have significantly fewer escape genes compared with humans. Furthermore, escape genes did not cluster in mouse, unlike the large escape domains in human, suggesting that expression is controlled at the level of individual genes. Our findings are consistent with the striking differences in phenotypes between female mice and women with a single X chromosome—a near normal phenotype in mice versus Turner syndrome and multiple abnormalities in humans. We found that escape genes are marked by the absence of trimethylation at lysine 27 of histone H3, a chromatin modification associated with genes subject to X inactivation. Furthermore, this epigenetic mark is developmentally regulated for some mouse genes.

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Section: Discussionsupporting

confidence: 92%

Global survey of escape from X inactivation by RNA-sequencing in mouse

Yang¹,

Babak²,

Shendure³

et al. 2010

Genome Res.

320

400

View full text Add to dashboard Cite

show abstract

“…Consistent with this idea, we have found a lesser enrichment in AT motifs at escape genes, perhaps explaining a lack of Xist coating (Murakami et al 2009). AT motifs may also be important for maintenance of silencing by recruiting AT-binding proteins involved in chromatin scaffolding.…”

Section: Genome Research 405supporting

confidence: 86%

Clcn4-2 genomic structure differs between the X locus in Mus spretus and the autosomal locus in Mus musculus: AT motif enrichment on the X

et al. 2011

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In Mus spretus, the chloride channel 4 gene Clcn4-2 is X-linked and dosage compensated by X up-regulation and X inactivation, while in the closely related mouse species Mus musculus, Clcn4-2 has been translocated to chromosome 7. We sequenced Clcn4-2 in M. spretus and identified the breakpoints of the evolutionary translocation in the Mus lineage. Genetic and epigenetic differences were observed between the 59ends of the autosomal and X-linked loci. Remarkably, Clcn4-2 introns have been truncated on chromosome 7 in M. musculus as compared with the X-linked loci from seven other eutherian mammals. Intron sequences specifically preserved in the X-linked loci were significantly enriched in AT-rich oligomers. Genome-wide analyses showed an overall enrichment in AT motifs unique to the eutherian X (except for genes that escape X inactivation), suggesting a role for these motifs in regulation of the X chromosome.[Supplemental material is available for this article. The sequencing data from this study have been submitted to GenBank (http://www.ncbi.nlm.nih.gov/Genbank/) under accession nos. HM053970 and HM053971.] In mammals, X-linked genes are regulated by special epigenetic mechanisms, because females have two X chromosomes and males only have one, while autosomes are present in two copies. These regulatory mechanisms are (1) X up-regulation in both sexes to balance expression between X-linked and autosomal genes (Gupta et al. 2006;Nguyen and Disteche 2006) and (2) X inactivation in females (Lyon 1961). Ohno (1967) predicted that due to these unique regulatory mechanisms the gene content of the X chromosome would be highly conserved between mammalian species. The chloride channel 4 gene (hereafter called Clcn4 when considering multiple mammalian species) illustrates a rare exception to this conservation, since it is X-linked in most mammals including human, primates, dog, cow, and horse (CLCN4), as well as rat (Clcn4-2), but located on chromosome 7 in the laboratory mouse (Clcn4-2) (derived from a mixture of M. musculus musculus and M. musculus domesticus and thereafter referred to as M. musculus) (Palmer et al. 1995;Rugarli et al. 1995;Flicek et al. 2010).Clcn4-2 is X-linked in the wild-derived mouse M. spretus, suggesting that it was translocated to an autosome in one branch of Mus (musculus) during evolution (Palmer et al. 1995;Rugarli et al. 1995). We have previously used F1 mice from crosses between Mus species to show that Clcn4-2 is subject to X inactivation (Rugarli et al. 1995) and that its expression is doubled on the active X from M. spretus compared with each autosomal allele from M. musculus (Adler et al. 1997). Thus, Clcn4-2 is subject to both types of dosage-compensation mechanisms, X up-regulation, and X inactivation. The different location of this gene in closely related mouse species provides a system to explore whether X-linked genes differ from autosomal genes in terms of DNA sequence and epigenetic modifications. Our hypothesis based on studies in other organisms is that specific sequence moti...

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“…Xist was first shown by RNA-FISH studies to coat the chromatin at the inactive X chromosome in a non-uniform manner, where euchromatic regions on the inactive X remained devoid of Xist coating in the initial stages of X-chromosome inactivation [56–58]. The physical association of Xist with chromatin was further confirmed by immunoprecipitation with antibodies against macroH2A1, a histone H2A variant enriched on the inactive X chromosome [59] (reviewed in [60]).…”

Section: The Promoters Of Genes Silenced By Lncrnas Are Covered With mentioning

confidence: 99%

Long non‐coding RNA modifies chromatin

2011

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Common themes are emerging in the molecular mechanisms of long non-coding RNA-mediated gene repression. Long non-coding RNAs (lncRNAs) participate in targeted gene silencing through chromatin remodelling, nuclear reorganisation, formation of a silencing domain and precise control over the entry of genes into silent compartments. The similarities suggest that these are fundamental processes of transcription regulation governed by lncRNAs. These findings have paved the way for analogous investigations on other lncRNAs and chromatin remodelling enzymes. Here we discuss these common mechanisms and provide our view on other molecules that warrant similar investigations. We also present our concepts on the possible mechanisms that may facilitate the exit of genes from the silencing domains and their potential therapeutic applications. Finally, we point to future areas of research and put forward our recommendations for improvements in resources and applications of existing technologies towards targeted outcomes in this active area of research.

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Identification of the Chromatin Regions Coated by Non-coding <i>Xist</i> RNA

Cited by 24 publications

References 52 publications

Global survey of escape from X inactivation by RNA-sequencing in mouse

Global survey of escape from X inactivation by RNA-sequencing in mouse

Clcn4-2 genomic structure differs between the X locus in Mus spretus and the autosomal locus in Mus musculus: AT motif enrichment on the X

Long non‐coding RNA modifies chromatin

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