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m6A RNA methylation promotes XIST-mediated transcriptional repression

Author

Listed:
  • Deepak P. Patil

    (Weill-Cornell Medical College, Cornell University)

  • Chun-Kan Chen

    (California Institute of Technology)

  • Brian F. Pickering

    (Weill-Cornell Medical College, Cornell University)

  • Amy Chow

    (California Institute of Technology)

  • Constanza Jackson

    (California Institute of Technology)

  • Mitchell Guttman

    (California Institute of Technology)

  • Samie R. Jaffrey

    (Weill-Cornell Medical College, Cornell University)

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.

Suggested Citation

  • Deepak P. Patil & Chun-Kan Chen & Brian F. Pickering & Amy Chow & Constanza Jackson & Mitchell Guttman & Samie R. Jaffrey, 2016. "m6A RNA methylation promotes XIST-mediated transcriptional repression," Nature, Nature, vol. 537(7620), pages 369-373, September.
    • Handle: RePEc:nat:nature:v:537:y:2016:i:7620:d:10.1038_nature19342
    DOI: 10.1038/nature19342
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    Cited by:

    1. Hyun Jung Hwang & Tae Lim Park & Hyeong-In Kim & Yeonkyoung Park & Geunhee Kim & Chiyeol Song & Won-Ki Cho & Yoon Ki Kim, 2023. "YTHDF2 facilitates aggresome formation via UPF1 in an m6A-independent manner," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Zhiyuan Luo & Jiacheng Zhang & Jingyi Fei & Shengdong Ke, 2022. "Deep learning modeling m6A deposition reveals the importance of downstream cis-element sequences," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Mi Zhang & Zsuzsanna Bodi & Katarzyna Mackinnon & Silin Zhong & Nathan Archer & Nigel P. Mongan & Gordon G. Simpson & Rupert G. Fray, 2022. "Two zinc finger proteins with functions in m6A writing interact with HAKAI," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Lisa-Marie Appel & Vedran Franke & Melania Bruno & Irina Grishkovskaya & Aiste Kasiliauskaite & Tanja Kaufmann & Ursula E. Schoeberl & Martin G. Puchinger & Sebastian Kostrhon & Carmen Ebenwaldner & M, 2021. "PHF3 regulates neuronal gene expression through the Pol II CTD reader domain SPOC," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    5. Lisa-Marie Appel & Vedran Franke & Johannes Benedum & Irina Grishkovskaya & Xué Strobl & Anton Polyansky & Gregor Ammann & Sebastian Platzer & Andrea Neudolt & Anna Wunder & Lena Walch & Stefanie Kais, 2023. "The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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