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

Autor: Kohei Koike, Kaichi Yoshizaki, Takako Kikkawa, Hisato Kobayashi, Shinya Oki, Ryuichi Kimura, Tomohiro Kono, Yasuhisa Matsui, Noriko Osumi, Kentaro Mochizuki, Hitoshi Inada, Lingling Mai
Rok vydání: 2021
Předmět:
Zdroj: EMBO Reports
ISSN: 1469-3178
1469-221X
DOI: 10.15252/embr.202051524
Popis: 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.
Paternal aging affects health and disease of the next generation, but the causative mechanisms are largely unknown. This study identifies hypo‐methylated sites enriched in REST/NRSF motifs in sperm DNA as epigenetic key features for inheritance.
Databáze: OpenAIRE
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