An adverse maternal environment (AME) predisposes adult offspring toward cognitive impairment in humans and mice. However, the underlying mechanisms remain poorly understood. Epigenetic changes in response to environmental exposure may be critical drivers of this change. Epigenetic regulators, including microRNAs, have been shown to affect cognitive function by altering hippocampal neurogenesis which is regulated in part by brain-derived neurotropic factor (BDNF). We sought to investigate the effects of AME on miR profile and their epigenetic characteristics, as well as neurogenesis and BDNF expression in mouse hippocampus. Using our mouse model of AME which is composed of maternal Western diet and prenatal environmental stress, we found that AME significantly increased hippocampal miR-10b-5p levels. We also found that AME significantly decreased DNA methylation and increased accumulations of active histone marks H3 lysine (K) 4me3, H3K14ac, and ­H3K36me3 at miR-10b promoter. Furthermore, AME significantly decreased hippocampal neurogenesis by decreasing cell numbers of Ki67⁺ (proliferation marker), NeuroD1⁺ (neuronal differentiation marker), and NeuN⁺ (mature neuronal marker) in the dentate gyrus (DG) region concurrently with decreased hippocampal BDNF protein levels. We speculate that the changes in epigenetic profile at miR-10b promoter may contribute to upregulation of miR-10b-5p and subsequently lead to decreased BDNF levels in a model of impaired offspring hippocampal neurogenesis and cognition in mice.
Dev Neurosci

中文翻译：

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不利的母体环境改变 MicroRNA-10b-5p 的表达及其表观遗传谱，同时损害雄性小鼠海马的海马神经发生

不利的母体环境 (AME) 使成年后代易患人类和小鼠的认知障碍。然而，潜在的机制仍然知之甚少。响应环境暴露的表观遗传变化可能是这种变化的关键驱动因素。包括 microRNA 在内的表观遗传调节因子已被证明通过改变海马神经发生来影响认知功能，而海马神经发生部分受脑源性神经营养因子 (BDNF) 的调节。我们试图研究 AME 对 miR 谱及其表观遗传特征的影响，以及小鼠海马中的神经发生和 BDNF 表达。使用由母体西方饮食和产前环境压力组成的 AME 小鼠模型，我们发现 AME 显着增加海马 miR-10b-5p 水平。我们还发现 AME 显着降低了 miR-10b 启动子的 DNA 甲基化并增加了活性组蛋白标记 H3 赖氨酸 (K) 4me3、H3K14ac 和 H3K36me3 的积累。此外，AME 通过减少 Ki67 的细胞数量显着降低海马神经发生⁺（增殖标志物）、NeuroD1 ⁺（神经元分化标志物）和 NeuN ⁺（成熟神经元标志物）在齿状回 (DG) 区域同时降低海马 BDNF 蛋白水平。我们推测 miR-10b 启动子表观遗传谱的变化可能有助于上调 miR-10b-5p 并随后导致小鼠海马神经发生和认知受损模型中的 BDNF 水平降低。
开发神经科学