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Title:
m6A RNA methylation promotes XIST-mediated transcriptional repression | Nature
Description:
The long non-coding RNA X-inactive specific transcript (XIST) mediates the transcriptional silencing of genes on the X chromosome. Here we show that, in human cells, XIST is highly methylated with at least 78 N6-methyladenosine (m6A) residues—a reversible base modification of unknown function in long non-coding RNAs. We show that m6A formation in XIST, as well as in cellular mRNAs, is mediated by RNA-binding motif protein 15 (RBM15) and its paralogue RBM15B, which bind the m6A-methylation complex and recruit it to specific sites in RNA. This results in the methylation of adenosine nucleotides in adjacent m6A consensus motifs. Furthermore, we show that knockdown of RBM15 and RBM15B, or knockdown of methyltransferase like 3 (METTL3), an m6A methyltransferase, impairs XIST-mediated gene silencing. A systematic comparison of m6A-binding proteins shows that YTH domain containing 1 (YTHDC1) preferentially recognizes m6A residues on XIST and is required for XIST function. Additionally, artificial tethering of YTHDC1 to XIST rescues XIST-mediated silencing upon loss of m6A. These data reveal a pathway of m6A formation and recognition required for XIST-mediated transcriptional repression. The methylation of adenosine residues on the long non-coding RNA XIST is essential for X-chromosome transcriptional repression during female mammalian development. The long non-coding RNA (lncRNA) known as XIST is required for the translational silencing of genes on one of the two X chromosomes during female mammalian development. Here, Samie Jaffrey and colleagues show that XIST is highly methylated, containing at least 78 N6-methyladenosine (m6A) residues throughout the length of the RNA. The XIST-binding protein RBM15 is shown to recruit the WTAP–METTL3 RNA m6A methyltransferase complex to XIST, and the nuclear m6A reader YTHDC1 is shown to activate gene-silencing mechanisms.
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nature portfolio permissions reprints privacy policy immunofluorescence-combined single-molecule rna-fish open-source platform accession number gse78030 advertising egfp-expressing shdc1-transfected cells promotes cap-independent translation social media female mammalian development author information authors u-rich rna-binding motifs sirbm15/sirbm15b double-knockdown sample primary micro rna wtap-dependent mettl3–rbm15/15b interaction epitranscriptome nature uracil-rich hnrnpc-binding motif transcriptome-wide rna-binding sites ejc-sr protein nexus n6-methyladenosine-dependent regulation reversible cross-linking combined representative rna-fish images activate gene-silencing mechanisms xist-mediated transcriptional repression mettl3/rbm15/15b-dependent manner single-nucleotide-resolution mapping nature 379 nature 521 nature 485 nature 505 nature 518 nature 537 nature xist-mediated transcriptional silencing xist-mediated gene silencing rbm15/15b–wtap–mettl3 complex x-linked gene silencing crispr-mediated homozygous knockout exploring deep-sequencing data weill-cornell medical college author correspondence rbm15/15b-binding sites show xist rna-mediated silencing rna n6-methyladenosine methyltransferase bio-imaging resource center pew-stewart scholars program rna n6-methyladenosine modification normal xist-induced silencing tailed mann–whitney test
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headline:m6A RNA methylation promotes XIST-mediated transcriptional repression
description:The long non-coding RNA X-inactive specific transcript (XIST) mediates the transcriptional silencing of genes on the X chromosome. Here we show that, in human cells, XIST is highly methylated with at least 78 N6-methyladenosine (m6A) residuesâa reversible base modification of unknown function in long non-coding RNAs. We show that m6A formation in XIST, as well as in cellular mRNAs, is mediated by RNA-binding motif protein 15 (RBM15) and its paralogue RBM15B, which bind the m6A-methylation complex and recruit it to specific sites in RNA. This results in the methylation of adenosine nucleotides in adjacent m6A consensus motifs. Furthermore, we show that knockdown of RBM15 and RBM15B, or knockdown of methyltransferase like 3 (METTL3), an m6A methyltransferase, impairs XIST-mediated gene silencing. A systematic comparison of m6A-binding proteins shows that YTH domain containing 1 (YTHDC1) preferentially recognizes m6A residues on XIST and is required for XIST function. Additionally, artificial tethering of YTHDC1 to XIST rescues XIST-mediated silencing upon loss of m6A. These data reveal a pathway of m6A formation and recognition required for XIST-mediated transcriptional repression. The methylation of adenosine residues on the long non-coding RNA XIST is essential for X-chromosome transcriptional repression during female mammalian development. The long non-coding RNA (lncRNA) known as XIST is required for the translational silencing of genes on one of the two X chromosomes during female mammalian development. Here, Samie Jaffrey and colleagues show that XIST is highly methylated, containing at least 78 N6-methyladenosine (m6A) residues throughout the length of the RNA. The XIST-binding protein RBM15 is shown to recruit the WTAPâMETTL3 RNA m6A methyltransferase complex to XIST, and the nuclear m6A reader YTHDC1 is shown to activate gene-silencing mechanisms.
datePublished:2016-09-07T00:00:00Z
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Gene silencing
Long non-coding RNAs
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RNA modification
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Humanities and Social Sciences
multidisciplinary
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headline:m6A RNA methylation promotes XIST-mediated transcriptional repression
description:The long non-coding RNA X-inactive specific transcript (XIST) mediates the transcriptional silencing of genes on the X chromosome. Here we show that, in human cells, XIST is highly methylated with at least 78 N6-methyladenosine (m6A) residuesâa reversible base modification of unknown function in long non-coding RNAs. We show that m6A formation in XIST, as well as in cellular mRNAs, is mediated by RNA-binding motif protein 15 (RBM15) and its paralogue RBM15B, which bind the m6A-methylation complex and recruit it to specific sites in RNA. This results in the methylation of adenosine nucleotides in adjacent m6A consensus motifs. Furthermore, we show that knockdown of RBM15 and RBM15B, or knockdown of methyltransferase like 3 (METTL3), an m6A methyltransferase, impairs XIST-mediated gene silencing. A systematic comparison of m6A-binding proteins shows that YTH domain containing 1 (YTHDC1) preferentially recognizes m6A residues on XIST and is required for XIST function. Additionally, artificial tethering of YTHDC1 to XIST rescues XIST-mediated silencing upon loss of m6A. These data reveal a pathway of m6A formation and recognition required for XIST-mediated transcriptional repression. The methylation of adenosine residues on the long non-coding RNA XIST is essential for X-chromosome transcriptional repression during female mammalian development. The long non-coding RNA (lncRNA) known as XIST is required for the translational silencing of genes on one of the two X chromosomes during female mammalian development. Here, Samie Jaffrey and colleagues show that XIST is highly methylated, containing at least 78 N6-methyladenosine (m6A) residues throughout the length of the RNA. The XIST-binding protein RBM15 is shown to recruit the WTAPâMETTL3 RNA m6A methyltransferase complex to XIST, and the nuclear m6A reader YTHDC1 is shown to activate gene-silencing mechanisms.
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Long non-coding RNAs
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multidisciplinary
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