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Nat Cell Biol. 2018 May;20(5):535-540. doi: 10.1038/s41556-018-0087-2. Epub 2018 Apr 25.

Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs.

Author information

1
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
2
Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV, USA.
3
University of Chinese Academy of Sciences, Beijing, China.
4
Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
5
Key Laboratory of Nutrition and Metabolism, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
6
College of Life Sciences, Shandong University of Technology, Zibo, China.
7
Nevada Proteomics Center, University of Nevada, Reno School of Medicine, Reno, NV, USA.
8
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. zhangying@ioz.ac.cn.
9
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. qzhou@ioz.ac.cn.
10
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. duane@ioz.ac.cn.
11
Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV, USA. cqi@med.unr.edu.

Abstract

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 1 . Increasing evidence now suggests that sperm small non-coding RNAs (sncRNAs) can mediate intergenerational transmission of paternally acquired phenotypes, including mental stress2,3 and metabolic disorders4-6. 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 (m5C, m2G) 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 m5C contributes to the secondary structure and biological properties of sncRNAs, implicating sperm RNA modifications as an additional layer of paternal hereditary information.

PMID:
29695786
PMCID:
PMC5926820
DOI:
10.1038/s41556-018-0087-2
[Indexed for MEDLINE]
Free PMC Article

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