m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • September 7, 2016

Research

keywords

  • Adenosine
  • Gene Silencing
  • RNA, Long Noncoding
  • Transcription, Genetic

Identity

PubMed Central ID

  • PMC5509218

Scopus Document Identifier

  • 84988329709

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2016.01.012

PubMed ID

  • 27602518

Additional Document Info

volume

  • 537

issue

  • 7620