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PMID: 27602518 Published · ppublish English Journal Article

m(6)A RNA methylation promotes XIST-mediated transcriptional repression.

Nature ·Vol. 537 ·No. 7620 ·2016-00-15 ·Pages 369-373

Patil DP, Chen CK, Pickering BF, Chow A, Jackson C, Guttman M, Jaffrey SR

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.

MeSH Terms
Adenosine/analogs & derivatives,metabolism Animals Cell Cycle Proteins Cell Line Embryonic Stem Cells/metabolism Female Gene Silencing HEK293 Cells Humans Male Methylation Methyltransferases/metabolism Mice Nerve Tissue Proteins/metabolism Nuclear Proteins/metabolism RNA Splicing Factors/metabolism RNA, Long Noncoding/genetics,metabolism RNA-Binding Proteins/metabolism Transcription, Genetic
Chemicals
Cell Cycle Proteins Nerve Tissue Proteins Nuclear Proteins RBM15 protein, human RNA Splicing Factors RNA, Long Noncoding RNA-Binding Proteins WTAP protein, human XIST non-coding RNA YTHDC1 protein, human N-methyladenosine Methyltransferases METTL3 protein, human Adenosine
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Patil Deepak P
Department of Pharmacology, Weill-Cornell Medical College, Cornell University, New York, New York 10065, USA.
Chen Chun-Kan
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Pickering Brian F
Department of Pharmacology, Weill-Cornell Medical College, Cornell University, New York, New York 10065, USA.
Chow Amy
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Jackson Constanza
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Guttman Mitchell
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Jaffrey Samie R
Department of Pharmacology, Weill-Cornell Medical College, Cornell University, New York, New York 10065, USA.
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature19342
Published
2016-00-15
Epub
2016-00-07
Pages
369-373
Language
English
Region
England
NLM ID
0410462
PMCID
PMC5509218
Subset
IM
Grants
NIH HHS · DP5 OD012190 · United States
NCI NIH HHS · R01 CA186702 · United States
NCI NIH HHS · T32 CA062948 · United States
NIGMS NIH HHS · T32 GM007616 · United States
Corrections
CommentIn
PMID: 28063638
CommentIn
PMID: 28384367
External Links
PubMed source DOI: 10.1038/nature19342 PMC Full Text View journal details
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