Medical Microbiology and Immunology, Genome Center, University of California, Davis, Davis, California, 95616.
MIND Institute, University of California, Davis, 2825 50th Street, Sacramento, California, 95817.
Glia. 2018 Mar;66(3):505-521. doi: 10.1002/glia.23261. Epub 2017 Nov 14.
Dysregulation in immune responses during pregnancy increases the risk of a having a child with an autism spectrum disorder (ASD). Asthma is one of the most common chronic diseases among pregnant women, and symptoms often worsen during pregnancy. We recently developed a mouse model of maternal allergic asthma (MAA) that induces changes in sociability, repetitive, and perseverative behaviors in the offspring. Since epigenetic changes help a static genome adapt to the maternal environment, activation of the immune system may epigenetically alter fetal microglia, the brain's resident immune cells. We therefore tested the hypothesis that epigenomic alterations to microglia may be involved in behavioral abnormalities observed in MAA offspring. We used the genome-wide approaches of whole genome bisulfite sequencing to examine DNA methylation and RNA sequencing to examine gene expression in microglia from juvenile MAA offspring. Differentially methylated regions were enriched for immune signaling pathways and important microglial developmental transcription factor binding motifs. Differential expression analysis identified genes involved in controlling microglial sensitivity to the environment and shaping neuronal connections in the developing brain. Differentially expressed genes significantly overlapped genes with altered expression in human ASD cortex, supporting a role for microglia in the pathogenesis of ASD.
在怀孕期间，免疫反应失调会增加孩子患自闭症谱系障碍（ASD）的风险。哮喘是孕妇中最常见的慢性疾病之一，其症状在怀孕期间往往会加重。我们最近开发了一种母源过敏性哮喘（MAA）的小鼠模型，该模型会导致后代出现社交能力、重复和坚持行为的变化。由于表观遗传变化有助于静态基因组适应母体环境，免疫系统的激活可能会使胎儿小胶质细胞（大脑中的常驻免疫细胞）发生表观遗传改变。因此，我们假设微胶质细胞的表观遗传改变可能与 MAA 后代观察到的行为异常有关。我们使用全基因组亚硫酸氢盐测序的全基因组方法来检测小胶质细胞中的 DNA 甲基化，以及使用 RNA 测序来检测小胶质细胞中的基因表达。差异甲基化区域富集了免疫信号通路和重要的小胶质细胞发育转录因子结合基序。差异表达分析确定了参与控制小胶质细胞对环境敏感性和塑造发育中大脑神经元连接的基因。差异表达的基因与人类 ASD 皮质中表达改变的基因显著重叠，支持小胶质细胞在 ASD 发病机制中的作用。
