m6A RNA methylation promotes XIST-mediated transcriptional repression
Open accessAbstract
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 N 6-methyladenosine (m 6 A) residues-a reversible base modification of unknown function in long non-coding RNAs. We show that m 6 A 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 m 6 A-methylation complex and recruit it to specific sites in RNA. This results in the methylation of adenosine nucleotides in adjacent m 6 A consensus motifs. Furthermore, we show that knockdown of RBM15 and RBM15B, or knockdown of methyltransferase like 3 (METTL3), an m 6 A methyltransferase, impairs XIST-mediated gene silencing. A systematic comparison of m 6 A-binding proteins shows that YTH domain containing 1 (YTHDC1) preferentially recognizes m 6 A residues on XIST and is required for XIST function. Additionally, artificial tethering of YTHDC1 to XIST rescues XIST-mediated silencing upon loss of m 6 A. These data reveal a pathway of m 6 A formation and recognition required for XIST-mediated transcriptional repression.
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“Additional components such as RBM15, KIAA1429, and ZC3H13 have been identified as part of the larger m6A writer complex [21–23].”
- Authors
- Patil, D. P., Chen, C.-K., Pickering, B. F., Chow, A., Jackson, C., Guttman, M., & Jaffrey, S. R.
- Affiliations
- Cornell University (US)
- California Institute of Technology (US)
- Corresponding author
- Jaffrey, Samie R.
- Venue
- Nature
- Published
- 2016-09
- Volume
- 537
- Issue
- 7620
- Pages
- 369-373
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5509218
- OpenAlex
- W2509465044
- Cited by
- 1,747
- References
- 53
- Citations by year
- 2026: 125 · 2025: 162 · 2024: 228 · 2023: 241 · 2022: 252 · 2021: 269 · 2020: 175 · 2019: 115 · 2018: 93 · 2017: 75 · 2016: 11
- FWCI
- 50.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (DP5OD012190)
- National Cancer Institute (T32CA062948, R01CA186702)
- National Institute of General Medical Sciences (T32GM007616)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- XIST, N6-methyladenosine, RNA methylation, long non-coding RNA, X chromosome inactivation, transcriptional repression, RBM15, RBM15B, METTL3, YTHDC1, m6A reader proteins, WTAP, X inactivation center
- MeSH terms
- RNA Splicing Factors, Adenosine, Animals, Cell Line, Female, Humans, Male, Methylation, Methyltransferases, Nerve Tissue Proteins, Nuclear Proteins, Transcription, Genetic, RNA-Binding Proteins, Cell Cycle Proteins, Gene Silencing, Mice, Embryonic Stem Cells, HEK293 Cells, RNA, Long Noncoding
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