Genome-Wide DNA Methylation Analysis Reveals Epigenetic Pattern of SH2B1 in Chinese Monozygotic Twins Discordant for Autism Spectrum Disorder
Genome-Wide DNA Methylation Analysis Reveals Epigenetic Pattern of SH2B1 in Chinese Monozygotic Twins Discordant for Autism Spectrum Disorder
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DOI：
10.3389/fnins.2019.00712
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发表时间：
2019-07-17
影响因子：
4.3
通讯作者：
Wu, Lijie
中科院分区：
文献类型：
--
作者：
Liang, Shuang;Li, Zhenzhi;Wu, Lijie
自闭症谱系障碍（ASD）是一种复杂的神经发育障碍。在ASD中已经观察到异常的DNA甲基化，但其机制在很大程度上仍然未知。在这里，我们采用不一致的单卵双胞胎来研究DNA甲基化对ASD病因的贡献。全基因组DNA甲基化分析使用从五对ASD不一致的单卵双胞胎中获得的样本进行，共发现2，397个差异甲基化基因。此外，这样的基因列表用基因和基因组的京都百科全书注释，并且证明在ASD不一致的单卵双胞胎中神经营养因子信号传导途径的主要激活。通过亚硫酸氢盐焦磷酸测序进一步证实了ASD不一致、ASD一致单卵双生子和一组30对散发病例对照中SH2B1基因的甲基化。结果表明，ASD不一致的单卵双生子的DNA甲基化差异大于ASD一致的单卵双生子。此外，SH2B1的Chr. 16：28856743的验证显示病例和对照之间的DNA甲基化存在显著差异。这些结果表明SH2B1异常甲基化与ASD病因学相关。提示SH2B1及其相关基因在ASD发病中的作用值得进一步研究。
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Aberrant DNA methylation has been observed in ASD but the mechanisms remain largely unknown. Here, we employed discordant monozygotic twins to investigate the contribution of DNA methylation to ASD etiology. Genome-wide DNA methylation analysis was performed using samples obtained from five pairs of ASD-discordant monozygotic twins, which revealed a total of 2,397 differentially methylated genes. Further, such gene list was annotated with Kyoto Encyclopedia of Genes and Genomes and demonstrated predominant activation of neurotrophin signaling pathway in ASD-discordant monozygotic twins. The methylation of SH2B1 gene was further confirmed in the ASD-discordant, ASD-concordant monozygotic twins, and a set of 30 pairs of sporadic case-control by bisulfite-pyrosequencing. The results showed that there was a greater DNA methylation difference in ASD-discordant monozygotic twins than ASD-concordant monozygotic twins. Further, verification of the Chr.16:28856743 of SH2B1 showed significant differences in DNA methylation between case and control. These results suggest abnormal methylation of SH2B1 is associated with ASD etiology. Our data suggest that it might be worthwhile to further explore the functions of SH2B1 and related genes of neurotrophin signaling pathway in ASD.