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

The discovery of RNAs (e.g. mRNAs, non-coding RNAs) in sperm has opened the possibility that sperm may function in 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 stress(2, 3) and metabolic disorders(4–6). 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 (HFD)-induced metabolic disorders to offspring. Dnmt2 deletion prevented the elevation of RNA modifications (m(5)C, m(2)G) in sperm 30–40nt RNA fractions that are induced by HFD. Also, Dnmt2 deletion altered the sperm small RNA expression profile, including levels of tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNA-28S), which might be essential in composing a sperm RNA ‘coding signature’ that is needed for paternal epigenetic memory. Finally, we show that Dnmt2-mediated m(5)C contributes to the secondary structure and biological properties of sncRNAs, implicating sperm RNA modifications as an additional layer of paternal hereditary information.