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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
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    Citations

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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. Haiyan Zhang & Xiaojing Luo & Wei Yang & Zhiying Wu & Zhicong Zhao & Xin Pei & Xue Zhang & Chonghao Chen & Josh Haipeng Lei & Qingxia Shi & Qi Zhao & Yanxing Chen & Wenwei Wu & Zhaolei Zeng & Huai-Qia, 2024. "YTHDF2 upregulation and subcellular localization dictate CD8 T cell polyfunctionality in anti-tumor immunity," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. 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.
    8. 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.

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