m6A RNA methylation promotesXIST-mediated transcriptional repression

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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,XISTis highly methylated with at least 78N6-methyladenosine (m6A) residues—a reversible base modification of unknown function in long non-coding RNAs. We show that m6A formation inXIST, 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 ofRBM15andRBM15B, or knockdown of methyltransferase like 3 (METTL3), an m6A methyltransferase, impairsXIST-mediated gene silencing. A systematic comparison of m6A-binding proteins shows that YTH domain containing 1 (YTHDC1) preferentially recognizes m6A residues onXISTand is required forXISTfunction. Additionally, artificial tethering of YTHDC1 toXISTrescuesXIST-mediated silencing upon loss of m6A. These data reveal a pathway of m6A formation and recognition required forXIST-mediated transcriptional repression.

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