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

Yunfang Zhang | Xudong Zhang | Junchao Shi | Francesca Tuorto | Xin Li | Yusheng Liu | Reinhard Liebers | Liwen Zhang | Yongcun Qu | Jingjing Qian | Maya Pahima | Ying Liu | Menghong Yan | Zhonghong Cao | Xiaohua Lei | Yujing Cao | Hongying Peng | Shichao Liu | Yue Wang | Huili Zheng | Rebekah Woolsey | David Quilici | Qiwei Zhai | Lei Li | Tong Zhou | Wei Yan | Frank Lyko | Ying Zhang | Qi Zhou | Enkui Duan | Qi Chen
Nature cell biology | 2018

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.

Pubmed ID: 29695786

Research resources used in this publication

None found

Antibodies used in this publication

None found

Associated grants

  • Agency: NICHD NIH HHS, United States
    Id: R01 HD092431
  • Agency: NICHD NIH HHS, United States
    Id: R01 HD085506
  • Agency: NIGMS NIH HHS, United States
    Id: P20 GM103440
  • Agency: NIGMS NIH HHS, United States
    Id: P30 GM110767
  • Agency: NICHD NIH HHS, United States
    Id: R01 HD060858

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