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

doi:10.15252/embr.202051524

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

EMBO Rep. 2021 Feb 3;22(2):e51524. doi: 10.15252/embr.202051524. Epub 2021 Jan 5.

Authors

Kaichi Yoshizaki^{1

2}, Ryuichi Kimura^{1

3}, Hisato Kobayashi^{4

5

6}, Shinya Oki³, Takako Kikkawa¹, Lingling Mai¹, Kohei Koike^{1

7}, Kentaro Mochizuki^{1

8}, Hitoshi Inada^{1

9}, Yasuhisa Matsui^{6

8}, Tomohiro Kono^{6

10}, Noriko Osumi^{1

6}

Affiliations

¹ Department of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan.
² Department of Disease Model, Aichi Developmental Disability Center, Aichi, Japan.
³ Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁴ NODAI Genome Research Center, Tokyo University of Agriculture, Tokyo, Japan.
⁵ Department of Embryology, Nara Medical University, Nara, Japan.
⁶ The Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.
⁷ Department of Physiology, Center for Integrative Physiology and Molecular Medicine, Saarland University School of Medicine, Homburg, Germany.
⁸ Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
⁹ Laboratory of Health and Sports Science, Division of Biomedical Engineering for Health and Welfare, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan.
¹⁰ Department of Bioscience, Tokyo University of Agriculture, Tokyo, Japan.

Abstract

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.

Keywords: DNA hypo-methylation; REST/NRSF; paternal aging; transgenerational epigenetic inheritance; ultrasonic vocalization.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
DNA Methylation*
Epigenesis, Genetic
Fathers
Humans
Male
Mice
Paternal Age*
Spermatozoa / metabolism