m6A enhances the phase separation potential of mRNA
m6A enhances the phase separation potential of mRNA
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DOI：
10.1038/s41586-019-1374-1
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发表时间：
2019-07-18
期刊：
影响因子：
64.8
通讯作者：
Jaffrey, Samie R.
中科院分区：
文献类型：
--
作者：
Ries, Ryan J.;Zaccara, Sara;Jaffrey, Samie R.
N-6-甲基腺苷（m（6）A）是mRNA中最常见的修饰核苷酸（1，2），约25%的mRNA含有至少一个m（6）A。mRNA甲基化形成m（6）A是多种细胞和生理过程所必需的（3）。虽然m（6）A在mRNA中的存在可以以不同的方式影响其命运，但目前尚不清楚m（6）A如何指导这一过程，以及为什么m（6）A的作用在不同的细胞环境中会有所不同。在这里，我们表明，胞浆中的m（6）A结合蛋白YTHDF 1，YTHDF 2和YTHDF 3进行液-液相分离在体外和细胞。这种相分离被含有多个而非单个m（6）A残基的mRNA显著增强。多甲基化的mRNA作为YTHDF蛋白结合的多价支架，并置它们的低复杂性结构域，从而导致相分离。所得的mRNA-YTHDF复合物然后分配到不同的内源性相分离的隔室，如P体，应激颗粒或神经元RNA颗粒。m（6）A-mRNA受到区室特异性调节，包括mRNA稳定性和翻译的降低。这些研究揭示了细胞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-液相分离原理的支配。
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.