PT  - JOURNAL ARTICLE
AU  - Kaichi Yoshizaki
AU  - Tasuku Koike
AU  - Ryuichi Kimura
AU  - Takako Kikkawa
AU  - Shinya Oki
AU  - Kohei Koike
AU  - Kentaro Mochizuki
AU  - Hitoshi Inada
AU  - Hisato Kobayashi
AU  - Yasuhisa Matsui
AU  - Tomohiro Kono
AU  - Noriko Osumi
TI  - Paternal age affects offspring’s behavior possibly via an epigenetic mechanism recruiting a transcriptional repressor REST
AID  - 10.1101/550095
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 550095
4099  - http://biorxiv.org/content/early/2019/02/15/550095.short
4100  - http://biorxiv.org/content/early/2019/02/15/550095.full
AB  - Advanced paternal age has deleterious effects on mental health of next generation. Using a mouse model, we have confirmed that offspring derived from aged fathers showed impairments in behavior and abnormalities in the brain structure and activity. Comprehensive target DNA methylome analyses revealed in aged sperm more hypo-methylated genomic regions, in which REST/NRSF binding motif was enriched. Gene set enrichment analyses also identified enrichment of “REST/NRSF target genes”, in addition to “Late-fetal genes” and autism spectrum disorder-related “SFARI genes”, in up-regulated genes of developing brains from aged father. Indeed, gene sets near hypo-methylated genomic regions with REST/NRSF binding motif were also enriched in up-regulated genes of developing brains. Taken altogether, DNA hypo-methylation due to paternal aging in sperm will induce leaky expression of REST/NRSF target genes in the developing brain, thereby causing neuronal abnormalities and subsequent behavioral alteration in offspring.