Division of Animal Sciences, University of Missouri, Columbia, Missouri, USA.
MU Institute for Data Science and Informatics, University of Missouri, Columbia, Missouri, USA.
FASEB J. 2022 Aug;36(8):e22463. doi: 10.1096/fj.202200255RR.
DNA methylation plays crucial roles during fetal development as well as aging. Whether the aging of the brain is programmed at the fetal stage remains untested. To test this hypothesis, mouse epigenetic clock (epiclock) was profiled in fetal (gestation day 15), postnatal (day 5), and aging (week 70) brain of male and female C57BL/6J inbred mice. Data analysis showed that on week 70, the female brain was epigenetically younger than the male brain. Predictive modeling by neural network identified specific methylations in the brain at the developing stages that were predictive of epigenetic state of the brain during aging. Transcriptomic analysis showed coordinated changes in the expression of epiclock genes in the fetal brain relative to the placenta. Whole-genome bisulfite sequencing identified sites that were methylated both in the placenta and fetal brain in a sex-specific manner. Epiclock genes and genes associated with specific signaling pathways, primarily the gonadotropin-releasing hormone receptor (GnRHR) pathway, were associated with the sex-bias methylations in the placenta as well as the fetal brain. Transcriptional crosstalk among the epiclock and GnRHR pathway genes was evident in the placenta that was maintained in the brain during development as well as aging. Collectively, these findings suggest that sex differences in the aging of the brain are of fetal origin and epigenetically linked to the placenta.
DNA 甲基化在胎儿发育和衰老过程中发挥着关键作用。大脑的衰老是否在胎儿期就已经被编程，目前尚未得到验证。为了验证这一假设，我们对雄性和雌性 C57BL/6J 近交系小鼠的胎儿（妊娠第 15 天）、新生（第 5 天）和衰老（第 70 周）大脑中的小鼠表观遗传钟（epiclock）进行了分析。数据分析显示，在第 70 周时，雌性大脑的表观遗传学年龄比雄性大脑年轻。神经网络预测模型确定了在发育阶段大脑中具有预测性的特定甲基化，这些甲基化可预测大脑在衰老过程中的表观遗传状态。转录组分析显示，相对于胎盘，胎儿大脑中 epiclock 基因的表达发生了协调变化。全基因组亚硫酸氢盐测序确定了胎盘和胎儿大脑中以性别特异性方式甲基化的位点。Epiclock 基因和与特定信号通路（主要是促性腺激素释放激素受体（GnRHR）通路）相关的基因与胎盘以及胎儿大脑中的性别偏倚甲基化有关。在胎盘和大脑发育以及衰老过程中，epiclock 和 GnRHR 通路基因之间存在明显的转录串扰。总之，这些发现表明大脑衰老的性别差异源于胎儿期，并与胎盘的表观遗传有关。
