Bar Ilan University Faculty of Medicine, Hanrietta Sold 8, Safed 13215, Israel.
Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
Cereb Cortex. 2017 Dec 1;27(12):5739-5754. doi: 10.1093/cercor/bhx250.
Autism Spectrum Disorder (ASD) is a complex neuropsychiatric syndrome whose etiology includes genetic and environmental components. Since epigenetic marks are sensitive to environmental insult, they may be involved in the development of ASD. Initial brain studies have suggested a dysregulation of epigenetic marks in ASD. However, due to cellular heterogeneity in the brain, these studies have not determined if there is a true change in the neuronal epigenetic signature. Here, we report a genome-wide methylation study on fluorescence-activated cell sorting-sorted neuronal nuclei from the frontal cortex of 16 male ASD and 15 male control subjects. Using the 450 K BeadArray, we identified 58 differentially methylated regions (DMRs) that included loci associated to GABAergic system genes, particularly ABAT and GABBR1, and brain-specific MicroRNAs. Selected DMRs were validated by targeted Next Generation Bisulfite Sequencing. Weighted gene correlation network analysis detected 3 co-methylation modules which are significantly correlated to ASD that were enriched for genomic regions underlying neuronal, GABAergic, and immune system genes. Finally, we determined an overlap of the 58 ASD-related DMRs with neurodevelopment associated DMRs. This investigation identifies alterations in the DNA methylation pattern in ASD cortical neurons, providing further evidence that epigenetic alterations in disorder-relevant tissues may be involved in the biology of ASD.
自闭症谱系障碍（ASD）是一种复杂的神经精神综合征，其病因包括遗传和环境因素。由于表观遗传标记对环境损伤敏感，它们可能参与 ASD 的发生。最初的大脑研究表明，ASD 中存在表观遗传标记的失调。然而，由于大脑中的细胞异质性，这些研究尚未确定神经元表观遗传特征是否真的发生了变化。在这里，我们报告了一项针对来自 16 名男性 ASD 患者和 15 名男性对照者额叶皮层的荧光激活细胞分选分离的神经元核的全基因组甲基化研究。使用 450 K BeadArray，我们鉴定了 58 个差异甲基化区域（DMR），其中包括与 GABA 能系统基因相关的基因座，特别是 ABAT 和 GABBR1，以及大脑特异性 MicroRNAs。通过靶向下一代焦磷酸测序验证了选定的 DMR。加权基因相关网络分析检测到 3 个与 ASD 显著相关的共甲基化模块，这些模块富含神经元、GABA 能和免疫系统基因的基因组区域。最后，我们确定了 58 个与 ASD 相关的 DMR 与神经发育相关 DMR 之间的重叠。这项研究确定了 ASD 皮质神经元中 DNA 甲基化模式的改变，进一步证明了与疾病相关组织中的表观遗传改变可能与 ASD 的生物学有关。
