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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / blood
  • Blood Glucose / metabolism
  • DNA (Cytosine-5-)-Methyltransferases / deficiency
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism*
  • Diet, High-Fat
  • Epigenesis, Genetic
  • Gene Expression Regulation, Developmental
  • Gene-Environment Interaction
  • Genetic Predisposition to Disease
  • Glucose Metabolism Disorders / blood
  • Glucose Metabolism Disorders / diagnosis
  • Glucose Metabolism Disorders / enzymology*
  • Glucose Metabolism Disorders / genetics*
  • Heredity
  • Insulin / blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NIH 3T3 Cells
  • Nucleic Acid Conformation
  • Paternal Inheritance*
  • Phenotype
  • RNA, Small Untranslated / chemistry
  • RNA, Small Untranslated / genetics*
  • RNA, Small Untranslated / metabolism
  • Spermatozoa / enzymology*
  • Structure-Activity Relationship
  • Transcriptome

Substances

  • Biomarkers
  • Blood Glucose
  • Insulin
  • RNA, Small Untranslated
  • Dnmt2 protein, mouse
  • DNA (Cytosine-5-)-Methyltransferases