Wang Xuelai, Liang Shuang, Sun Yi, Li Haixin, Endo Fumio, Nakao Mitsuyoshi, Saitoh Noriko, Wu Lijie
Department of Child and Adolescent Health, School of Public Health, Harbin Medical University, No.157 Baojian Road, Harbin, 150081, China.
Department of Pediatrics, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
Metab Brain Dis. 2017 Aug;32(4):1033-1042. doi: 10.1007/s11011-017-9990-7. Epub 2017 Mar 16.
Autism spectrum disorder (ASD) is a neurodevelopment disorder with abnormalities of social interaction, communication and repetitive behaviors. The higher prevalence of ASD in men implies a potential relationship between sex hormones and ASD etiology. The ESR2 gene encodes estrogen receptor beta (ESR2) and plays an important role during brain development. A relationship between ESR2 and ASD has been suggested by studies on single nucleotide polymorphisms and mRNA and protein expression levels in ASD patients. Here, we explored the possible epigenetic regulation of the ESR2 gene in autism. We collected genomic DNA from the peripheral blood of Chinese Han males with autism and age-matched normal males and measured DNA methylation of CpG islands in the ESR2 gene, which consisted of 41 CpG sites among the proximal promoter region and an untranslated exon, by bisulfite sequencing. We also investigated a relationship between DNA methylation and phenotypic features of autism, as assessed by the Children Autism Rating Scale. We found little overall difference in the DNA methylation of the ESR2 5'-flanking region in individuals with autism compared with normal individuals. However, detailed analyses revealed that eight specific CpG sites were hypermethylated in autistic individuals and that four specific CpG sites were positively associated with the severity of autistic symptoms. Our study indicates that the epigenetic dysregulation of ESR2 may govern the development of autism.
自闭症谱系障碍（ASD）是一种神经发育障碍，伴有社交互动、沟通和重复行为异常。男性中ASD的患病率较高，这意味着性激素与ASD病因之间可能存在关联。ESR2基因编码雌激素受体β（ESR2），在大脑发育过程中起重要作用。对ASD患者单核苷酸多态性以及mRNA和蛋白质表达水平的研究表明ESR2与ASD之间存在关联。在此，我们探讨了自闭症中ESR2基因可能的表观遗传调控。我们从患有自闭症的中国汉族男性和年龄匹配的正常男性的外周血中收集基因组DNA，并通过亚硫酸氢盐测序测量ESR2基因中CpG岛的DNA甲基化，该基因在近端启动子区域和一个非翻译外显子中共有41个CpG位点。我们还通过儿童自闭症评定量表评估了DNA甲基化与自闭症表型特征之间的关系。我们发现，与正常个体相比，自闭症个体ESR2 5'侧翼区域的DNA甲基化总体差异不大。然而，详细分析显示，自闭症个体中有八个特定的CpG位点发生了高甲基化，并且有四个特定的CpG位点与自闭症症状的严重程度呈正相关。我们的研究表明，ESR2的表观遗传失调可能影响自闭症的发展。
