RT Journal Article
SR Electronic
T1 Paternal age affects offspring’s behavior possibly via an epigenetic mechanism recruiting a transcriptional repressor REST
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 550095
DO 10.1101/550095
A1 Kaichi Yoshizaki
A1 Tasuku Koike
A1 Ryuichi Kimura
A1 Takako Kikkawa
A1 Shinya Oki
A1 Kohei Koike
A1 Kentaro Mochizuki
A1 Hitoshi Inada
A1 Hisato Kobayashi
A1 Yasuhisa Matsui
A1 Tomohiro Kono
A1 Noriko Osumi
YR 2019
UL http://biorxiv.org/content/early/2019/02/15/550095.abstract
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.