IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v571y2019i7765d10.1038_s41586-019-1374-1.html
   My bibliography  Save this article

m6A enhances the phase separation potential of mRNA

Author

Listed:
  • Ryan J. Ries

    (Cornell University)

  • Sara Zaccara

    (Cornell University)

  • Pierre Klein

    (Cornell University)

  • Anthony Olarerin-George

    (Cornell University)

  • Sim Namkoong

    (University of Michigan)

  • Brian F. Pickering

    (Cornell University)

  • Deepak P. Patil

    (Cornell University)

  • Hojoong Kwak

    (Cornell University)

  • Jun Hee Lee

    (University of Michigan)

  • Samie R. Jaffrey

    (Cornell University)

Abstract

N6-methyladenosine (m6A) is the most prevalent modified nucleotide in mRNA1,2, with around 25% of mRNAs containing at least one m6A. Methylation of mRNA to form m6A is required for diverse cellular and physiological processes3. Although the presence of m6A in an mRNA can affect its fate in different ways, it is unclear how m6A directs this process and why the effects of m6A can vary in different cellular contexts. Here we show that the cytosolic m6A-binding proteins—YTHDF1, YTHDF2 and YTHDF3—undergo liquid–liquid phase separation in vitro and in cells. This phase separation is markedly enhanced by mRNAs that contain multiple, but not single, m6A residues. Polymethylated mRNAs act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their low-complexity domains and thereby leading to phase separation. The resulting mRNA–YTHDF complexes then partition into different endogenous phase-separated compartments, such as P-bodies, stress granules or neuronal RNA granules. m6A-mRNA is subject to compartment-specific regulation, including a reduction in the stability and translation of mRNA. These studies reveal that the number and distribution of m6A sites in cellular mRNAs can regulate and influence the composition of the phase-separated transcriptome, and suggest that the cellular properties of m6A-modified mRNAs are governed by liquid–liquid phase separation principles.

Suggested Citation

  • Ryan J. Ries & Sara Zaccara & Pierre Klein & Anthony Olarerin-George & Sim Namkoong & Brian F. Pickering & Deepak P. Patil & Hojoong Kwak & Jun Hee Lee & Samie R. Jaffrey, 2019. "m6A enhances the phase separation potential of mRNA," Nature, Nature, vol. 571(7765), pages 424-428, July.
  • Handle: RePEc:nat:nature:v:571:y:2019:i:7765:d:10.1038_s41586-019-1374-1
    DOI: 10.1038/s41586-019-1374-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-019-1374-1
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-019-1374-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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. Dongmei Wang & Tao Sun & Yuan Xia & Zhe Zhao & Xue Sheng & Shuying Li & Yuechan Ma & Mingying Li & Xiuhua Su & Fan Zhang & Peng Li & Daoxin Ma & Jingjing Ye & Fei Lu & Chunyan Ji, 2023. "Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Ziqi Ren & Wei Tang & Luxin Peng & Peng Zou, 2023. "Profiling stress-triggered RNA condensation with photocatalytic proximity labeling," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Anthony Khong & Tyler Matheny & Thao Ngoc Huynh & Vincent Babl & Roy Parker, 2022. "Limited effects of m6A modification on mRNA partitioning into stress granules," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    5. Florian Pernin & Qiao-Ling Cui & Abdulshakour Mohammadnia & Milton G. F. Fernandes & Jeffery A. Hall & Myriam Srour & Roy W. R. Dudley & Stephanie E. J. Zandee & Wendy Klement & Alexandre Prat & Hanna, 2024. "Regulation of stress granule formation in human oligodendrocytes," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    6. Chen Wang & Hideki Tanizawa & Connor Hill & Aaron Havas & Qiang Zhang & Liping Liao & Xue Hao & Xue Lei & Lu Wang & Hao Nie & Yuan Qi & Bin Tian & Alessandro Gardini & Andrew V. Kossenkov & Aaron Gold, 2024. "METTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    7. Meng Xu & Dulmi Senanayaka & Rongwei Zhao & Tafadzwa Chigumira & Astha Tripathi & Jason Tones & Rachel M. Lackner & Anne R. Wondisford & Laurel N. Moneysmith & Alexander Hirschi & Sara Craig & Sahar A, 2024. "TERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cells," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:571:y:2019:i:7765:d:10.1038_s41586-019-1374-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.