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.

中文翻译：

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父本年龄通过涉及REST / NRSF的表观遗传机制影响后代

父辈高龄会对下一代的各种特征产生有害影响。在这里，我们在小鼠中建立了父系衰老模型，以了解转基因表观遗传学的分子机制。老年小鼠精子的全基因组靶DNA甲基基因组分析显示，更多的低甲基化基因组区域富含REST / NRSF结合基序。基因集富集分析还揭示了老年父亲胚胎前脑中REST / NRSF靶基因的上调。用DNA脱甲基化药物表型给药的幼鼠衍生的后代，由年迈的父亲衍生的幼仔的声音交流异常。总之，精子DNA的甲基化不足可能是引起REST / NRSF目标基因表达波动的关键分子特征，可调节子代的神经发育程序。