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

  • Author(s): Zhang, Yunfang
  • Zhang, Xudong
  • Shi, Junchao
  • Tuorto, Francesca
  • Li, Xin
  • Liu, Yusheng
  • Liebers, Reinhard
  • Zhang, Liwen
  • Qu, Yongcun
  • Qian, Jingjing
  • Pahima, Maya
  • Liu, Ying
  • Yan, Menghong
  • Cao, Zhonghong
  • Lei, Xiaohua
  • Cao, Yujing
  • Peng, Hongying
  • Liu, Shichao
  • Wang, Yue
  • Zheng, Huili
  • Woolsey, Rebekah
  • Quilici, David
  • Zhai, Qiwei
  • Li, Lei
  • Zhou, Tong
  • Yan, Wei
  • Lyko, Frank
  • Zhang, Ying
  • Zhou, Qi
  • Duan, Enkui
  • Chen, Qi
  • et al.
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.

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