Paternal age affects offspring via an epigenetic mechanism involving REST/NRSF

Kaichi Yoshizaki, Ryuichi Kimura, Hisato Kobayashi, Shinya Oki, Takako Kikkawa, Lingling Mai, Kohei Koike, Kentaro Mochizuki, Hitoshi Inada, Yasuhisa Matsui, Tomohiro Kono, Noriko Osumi

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


Advanced paternal age can have deleterious effects on various traits in the next generation. Here, we establish a paternal-aging model in mice to understand the molecular mechanisms of transgenerational epigenetics. Whole-genome target DNA methylome analyses of sperm from aged mice reveal more hypo-methylated genomic regions enriched in REST/NRSF binding motifs. Gene set enrichment analyses also reveal the upregulation of REST/NRSF target genes in the forebrain of embryos from aged fathers. Offspring derived from young mice administrated with a DNA de-methylation drug phenocopy the abnormal vocal communication of pups derived from aged fathers. In conclusion, hypo-methylation of sperm DNA can be a key molecular feature modulating neurodevelopmental programs in offspring by causing fluctuations in the expression of REST/NRSF target genes.

Original languageEnglish
Article numbere51524
JournalEMBO Reports
Issue number2
Publication statusPublished - 2021 Feb 3


  • DNA hypo-methylation
  • paternal aging
  • transgenerational epigenetic inheritance
  • ultrasonic vocalization

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics


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