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


Yoshizaki K(1)(2), Kimura R(1)(3), Kobayashi H(4)(5)(6), Oki S(3), Kikkawa T(1), Mai L(1), Koike K(1)(7), Mochizuki K(1)(8), Inada H(1)(9), Matsui Y(6)(8), Kono T(6)(10), Osumi N(1)(6).
Author information:
(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.


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.