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m~6 A enhances the phase separation potential of mRNA

机译：m〜6 A增强mRNA的相分离潜能

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摘要

N-6-methyladenosine (m(6)A) is the most prevalent modified nucleotide in mRNA(1,2), with around 25% of mRNAs containing at least one m(6)A. Methylation of mRNA to form m(6)A is required for diverse cellular and physiological processes(3). Although the presence of m(6)A in an mRNA can affect its fate in different ways, it is unclear how m(6)A directs this process and why the effects of m(6)A can vary in different cellular contexts. Here we show that the cytosolic m(6)A-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, m(6)A 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. m(6)A-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 m(6)A sites in cellular mRNAs can regulate and influence the composition of the phase-separated transcriptome, and suggest that the cellular properties of m(6)A-modified mRNAs are governed by liquid-liquid phase separation principles.
机译：N-6-甲基腺苷（m（6）A）是mRNA（1,2）中最普遍的修饰核苷酸，约25％的mRNA含有至少一个m（6）A。 mRNA的甲基化形成m（6）A是多种细胞和生理过程所必需的（3）。尽管mRNA中m（6）A的存在会以不同方式影响其命运，但尚不清楚m（6）A如何指导这一过程，以及为什么m（6）A的作用会在不同的细胞环境中发生变化。在这里我们显示胞质m（6）A结合蛋白-YTHDF1，YTHDF2和YTHDF3在体外和细胞中进行液-液相分离。包含多个但不单个m（6）A残基的mRNA显着增强了这种相分离。聚甲基化的mRNA作为YTHDF蛋白质结合的多价支架，将其低复杂度结构域并置，从而导致相分离。然后将所得的mRNA-YTHDF复合物分配到不同的内源相分离的区室中，例如P体，应激颗粒或神经元RNA颗粒。 m（6）A-mRNA受到隔室特异性调节，包括mRNA稳定性和翻译的降低。这些研究表明，细胞mRNA中m（6）A位点的数量和分布可以调节和影响相分离转录组的组成，并表明m（6）A修饰的mRNA的细胞特性受液体控制。 -液相分离原理。

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  • 来源
    《Nature》 |2019年第7765期|424-428|共5页
  • 作者

    Ries Ryan J.; Zaccara Sara; Klein Pierre; Olarerin-George Anthony; Namkoong Sim; Pickering Brian F.; Patil Deepak P.; Kwak Hojoong; Lee Jun Hee; Jaffrey Samie R.;

  • 作者单位

    Cornell Univ, Dept Pharmacol, Weill Cornell Med Coll, New York, NY 10021 USA;

    Cornell Univ, Dept Pharmacol, Weill Cornell Med Coll, New York, NY 10021 USA;

    Cornell Univ, Dept Pharmacol, Weill Cornell Med Coll, New York, NY 10021 USA;

    Cornell Univ, Dept Pharmacol, Weill Cornell Med Coll, New York, NY 10021 USA;

    Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA;

    Cornell Univ, Dept Pharmacol, Weill Cornell Med Coll, New York, NY 10021 USA;

    Cornell Univ, Dept Pharmacol, Weill Cornell Med Coll, New York, NY 10021 USA;

    Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY USA;

    Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA;

    Cornell Univ, Dept Pharmacol, Weill Cornell Med Coll, New York, NY 10021 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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