PNA interference mapping demonstrates functional domains in the noncoding RNA
            <i>Xist</i>

Beletskii, A. V.; Hong, Young‐Kwon; Pehrson, John R.; Egholm, Michael; Strauss, William

doi:10.1073/pnas.161173098

Cited by 106 publications

(79 citation statements)

References 41 publications

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“…In keeping, we propose that mH2A may bind RNA through its hinge domain, and the resulting negative charge caused by phosphorylation (T128ph, S137ph, and/or yet unidentified sites) might abrogate its ability to bind RNA, consistent with its exclusion from the Xi. Although the ability of mH2A (and its hinge domain) to bind RNA is unclear, several studies have shown that its localization to the Xi depends on the Xist RNA: conditional deletion of Xist during X inactivation or abolishing the ability of Xist to bind the Xi prevent mH2A association with the Xi, and ectopic expression of Xist on autosomes results in the recruitment of mH2A to these ectopic sites (39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

A phosphorylated subpopulation of the histone variant macroH2A1 is excluded from the inactive X chromosome and enriched during mitosis

Bernstein

Muratore-Schroeder²,

Diaz

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Histone variants play an important role in numerous biological processes through changes in nucleosome structure and stability and possibly through mechanisms influenced by posttranslational modifications unique to a histone variant. The family of histone H2A variants includes members such as H2A.Z, the DNA damageassociated H2A.X, macroH2A (mH2A), and H2ABbd (Barr bodydeficient). Here, we have undertaken the challenge to decipher the posttranslational modification-mediated ''histone code'' of mH2A, a variant generally associated with certain forms of condensed chromatin such as the inactive X chromosome in female mammals. By using female human cells as a source of mH2A, endogenous mH2A was purified and analyzed by mass spectrometry. Although mH2A is in low abundance compared with conventional histones, we identified a phosphorylation site, S137ph, which resides within the ''hinge'' region of mH2A. This lysine-rich hinge is an Ϸ30-aa stretch between the H2A and macro domains, proposed to bind nucleic acids. A specific antibody to S137ph was raised; by using this reagent, S137 phosphorylation was found to be present in both male and female cells and on both splice variants of the mH2A1 gene. Although mH2A is generally enriched on the inactive X chromosome in female cells, mH2AS137ph is excluded from this heterochromatic structure. Thus, a phosphorylated subpopulation of mH2A appears to play a unique role in chromatin regulation beyond X inactivation. We provide evidence that S137ph is enriched in mitosis, suggestive of a role in the regulation of mH2A posttranslational modifications throughout the cell cycle.macroH2A ͉ histone modifications ͉ phosphorylation

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Section: Discussionmentioning

confidence: 99%

A phosphorylated subpopulation of the histone variant macroH2A1 is excluded from the inactive X chromosome and enriched during mitosis

Bernstein

Muratore-Schroeder²,

Diaz

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…The origin of the A-repeat region was recently shown to have most likely originated as an endogenous retrovirus, ERVB5 (Elisaphenko et al 2008). In contrast, the localization of XIST seems to be dependent on sequences more dispersed throughout the transcript (Wutz et al 2002), although a later study using targeting antisense oligonucleotides implicated the murine-specific C-repeat region in correct targeting through unknown mechanisms (Beletskii et al 2001). This targeting is mediated by the specific interaction of repeat C with the transcription factor, YY1, that directs XIST to specific genomic loci through DNA binding (Jeon and Lee 2011).…”

Section: Direct Evidence For Te-derived Functional Domains In Lncrnasmentioning

confidence: 99%

The RIDL hypothesis: transposable elements as functional domains of long noncoding RNAs

Johnson

Guigó

2014

RNA

270

231

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Our genome contains tens of thousands of long noncoding RNAs (lncRNAs), many of which are likely to have genetic regulatory functions. It has been proposed that lncRNA are organized into combinations of discrete functional domains, but the nature of these and their identification remain elusive. One class of sequence elements that is enriched in lncRNA is represented by transposable elements (TEs), repetitive mobile genetic sequences that have contributed widely to genome evolution through a process termed exaptation. Here, we link these two concepts by proposing that exonic TEs act as RNA domains that are essential for lncRNA function. We term such elements Repeat Insertion Domains of LncRNAs (RIDLs). A growing number of RIDLs have been experimentally defined, where TE-derived fragments of lncRNA act as RNA-, DNA-, and protein-binding domains. We propose that these reflect a more general phenomenon of exaptation during lncRNA evolution, where inserted TE sequences are repurposed as recognition sites for both protein and nucleic acids. We discuss a series of genomic screens that may be used in the future to systematically discover RIDLs. The RIDL hypothesis has the potential to explain how functional evolution can keep pace with the rapid gene evolution observed in lncRNA. More practically, TE maps may in the future be used to predict lncRNA function.

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“…Repeat C is located 3 kb downstream of repeat A and contains 14 tandem repeats of a C-rich sequence with ∼90% interrepeat homology. Previous work showed that treating cells for 6 d with an antisense peptide nucleic acid (PNA) against repeat C led to loss of Xist from Xi heterochromatin (13), suggesting that the repeat C region may harbor an essential element. Curiously, it has also been shown that deleting repeat C on an Xist transgene has no effect on XCI (11).…”

mentioning

confidence: 99%

Locked nucleic acids (LNAs) reveal sequence requirements and kinetics of Xist RNA localization to the X chromosome

Sarma

Levasseur²,

Aristarkhov³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

143

107

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A large fraction of the mammalian genome is transcribed into long noncoding RNAs. The RNAs remain largely uncharacterized as the field awaits new technologies to aid functional analysis. Here, we describe a unique use of locked nucleic acids (LNAs) for studying nuclear long noncoding RNA, an RNA subclass that has been less amenable to traditional knockdown techniques. We target LNAs at Xist RNA and show displacement from the X chromosome with fast kinetics. Xist transcript stability is not affected. By targeting different Xist regions, we identify a localization domain and show that polycomb repressive complex 2 (PRC2) is displaced together with Xist. Thus, PRC2 depends on RNA for both initial targeting to and stable association with chromatin. H3K27-trimethyl marks and gene silencing remain stable. Time-course analysis of RNA relocalization suggests that Xist and PRC2 bind to different regions of the X at the same time but do not reach saturating levels immediately. Thus, LNAs provide a tool for studying an emerging class of regulatory RNA and offer a window of opportunity to target epigenetic modifications with possible therapeutic applications.dosage compensation | X inactivation

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PNA interference mapping demonstrates functional domains in the noncoding RNA Xist

Cited by 106 publications

References 41 publications

A phosphorylated subpopulation of the histone variant macroH2A1 is excluded from the inactive X chromosome and enriched during mitosis

A phosphorylated subpopulation of the histone variant macroH2A1 is excluded from the inactive X chromosome and enriched during mitosis

The RIDL hypothesis: transposable elements as functional domains of long noncoding RNAs

Locked nucleic acids (LNAs) reveal sequence requirements and kinetics of Xist RNA localization to the X chromosome

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