ATF7-Dependent Epigenetic Changes Are Required for the Intergenerational Effect of a Paternal Low-Protein Diet

Mol Cell. 2020 May 7;78(3):445-458.e6. doi: 10.1016/j.molcel.2020.02.028. Epub 2020 Mar 19.


Paternal dietary conditions may contribute to metabolic disorders in offspring. We have analyzed the role of the stress-dependent epigenetic regulator cyclic AMP-dependent transcription factor 7 (ATF7) in paternal low-protein diet (pLPD)-induced gene expression changes in mouse liver. Atf7+/- mutations cause an offspring phenotype similar to that caused by pLPD, and the effect of pLPD almost vanished when paternal Atf7+/- mice were used. ATF7 binds to the promoter regions of ∼2,300 genes, including cholesterol biosynthesis-related and tRNA genes in testicular germ cells (TGCs). LPD induces ATF7 phosphorylation by p38 via reactive oxygen species (ROS) in TGCs. This leads to the release of ATF7 and a decrease in histone H3K9 dimethylation (H3K9me2) on its target genes. These epigenetic changes are maintained and induce expression of some tRNA fragments in spermatozoa. These results indicate that LPD-induced and ATF7-dependent epigenetic changes in TGCs play an important role in paternal diet-induced metabolic reprograming in offspring.

Keywords: ATF7; ROS; cholesterol biosynthesis; epigenetic regulation; histone modification; intergenerational inheritance; paternal diet.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factors / genetics*
  • Activating Transcription Factors / metabolism
  • Animals
  • Diet, Protein-Restricted*
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Regulation
  • Histones / metabolism
  • Liver / physiology*
  • Lysine / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutation
  • Phosphorylation
  • Promoter Regions, Genetic
  • Spermatozoa / physiology*


  • ATF7 protein, mouse
  • Activating Transcription Factors
  • Histones
  • Lysine