State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV, USA.
Nat Cell Biol. 2018 May;20(5):535-540. doi: 10.1038/s41556-018-0087-2. Epub 2018 Apr 25.
The discovery of RNAs (for example, messenger RNAs, non-coding RNAs) in sperm has opened the possibility that sperm may function by delivering additional paternal information aside from solely providing the DNA . Increasing evidence now suggests that sperm small non-coding RNAs (sncRNAs) can mediate intergenerational transmission of paternally acquired phenotypes, including mental stress and metabolic disorders. How sperm sncRNAs encode paternal information remains unclear, but the mechanism may involve RNA modifications. Here we show that deletion of a mouse tRNA methyltransferase, DNMT2, abolished sperm sncRNA-mediated transmission of high-fat-diet-induced metabolic disorders to offspring. Dnmt2 deletion prevented the elevation of RNA modifications (mC, mG) in sperm 30-40 nt RNA fractions that are induced by a high-fat diet. Also, Dnmt2 deletion altered the sperm small RNA expression profile, including levels of tRNA-derived small RNAs and rRNA-derived small RNAs, which might be essential in composing a sperm RNA 'coding signature' that is needed for paternal epigenetic memory. Finally, we show that Dnmt2-mediated mC contributes to the secondary structure and biological properties of sncRNAs, implicating sperm RNA modifications as an additional layer of paternal hereditary information.
精子中 RNA（例如信使 RNA、非编码 RNA）的发现开辟了这样一种可能，即精子除了提供 DNA 之外，还可能通过传递额外的父系信息来发挥作用。越来越多的证据表明，精子小非编码 RNA（sncRNA）可以介导父系获得表型的跨代传递，包括精神压力和代谢紊乱。精子 sncRNA 如何编码父系信息尚不清楚，但该机制可能涉及 RNA 修饰。本文中，我们发现，一种小鼠 tRNA 甲基转移酶 DNMT2 的缺失，消除了精子 sncRNA 介导的高脂肪饮食诱导的代谢紊乱向后代的传递。Dnmt2 缺失阻止了高脂肪饮食诱导的精子 30-40nt RNA 片段中 RNA 修饰（mC、mG）的增加。此外，Dnmt2 缺失改变了精子小 RNA 的表达谱，包括 tRNA 衍生的小 RNA 和 rRNA 衍生的小 RNA 的水平，这些可能对于构成精子 RNA“编码特征”至关重要，该特征是父系表观遗传记忆所必需的。最后，我们发现 Dnmt2 介导的 mC 有助于 sncRNA 的二级结构和生物学特性，暗示精子 RNA 修饰是父系遗传信息的另一个层次。
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