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mA 增强了 mRNA 的相分离潜力。

mA enhances the phase separation potential of mRNA.

机构信息

Department of Pharmacology, Weill-Cornell Medical College, Cornell University, New York, NY, USA.

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.

出版信息

Nature. 2019 Jul;571(7765):424-428. doi: 10.1038/s41586-019-1374-1. Epub 2019 Jul 10.

DOI:10.1038/s41586-019-1374-1
PMID:31292544
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6662915/
Abstract

N-methyladenosine (mA) is the most prevalent modified nucleotide in mRNA, with around 25% of mRNAs containing at least one mA. Methylation of mRNA to form mA is required for diverse cellular and physiological processes. Although the presence of mA in an mRNA can affect its fate in different ways, it is unclear how mA directs this process and why the effects of mA can vary in different cellular contexts. Here we show that the cytosolic mA-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, mA 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. mA-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 mA sites in cellular mRNAs can regulate and influence the composition of the phase-separated transcriptome, and suggest that the cellular properties of mA-modified mRNAs are governed by liquid-liquid phase separation principles.

摘要

N6-甲基腺苷（m6A）是 mRNA 中最普遍存在的修饰核苷酸，约 25%的 mRNA 至少含有一个 m6A。mRNA 的甲基化形成 m6A 是多种细胞和生理过程所必需的。尽管 m6A 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 m6A 如何指导这一过程，以及为什么 m6A 的影响在不同的细胞环境中会有所不同。在这里，我们显示细胞质 m6A 结合蛋白-YTHDF1、YTHDF2 和 YTHDF3 在体外和细胞中发生液-液相分离。这种相分离明显受到含有多个、而不是单个 m6A 残基的 mRNAs 的增强。多甲基化的 mRNAs 作为 YTHDF 蛋白结合的多价支架，使它们的低复杂度结构域相邻，从而导致相分离。由此产生的 mRNA-YTHDF 复合物然后分配到不同的内源性相分离区室，如 P 体、应激颗粒或神经元 RNA 颗粒。m6A-mRNA 受到特定区室的调节，包括 mRNA 稳定性和翻译的降低。这些研究表明，细胞内 mRNAs 中 m6A 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 m6A 修饰的 mRNAs 的细胞特性受液-液相分离原则的控制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/496a/6662915/476118b073ee/nihms-1531920-f0004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/496a/6662915/e2adf920739a/nihms-1531920-f0006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/496a/6662915/f381605352ed/nihms-1531920-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/496a/6662915/2a36d23c8fdb/nihms-1531920-f0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/496a/6662915/89e120117afa/nihms-1531920-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/496a/6662915/8d285c7e6ba7/nihms-1531920-f0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/496a/6662915/476118b073ee/nihms-1531920-f0004.jpg

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