Complex epigenetic regulation of engrailed-2 (EN-2) homeobox gene in the autism cerebellum.
Complex epigenetic regulation of engrailed-2 (EN-2) homeobox gene in the autism cerebellum.
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DOI：
10.1038/tp.2013.8
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发表时间：
2013-02-19
影响因子：
6.8
通讯作者：
Pogribny IP
中科院分区：
文献类型：
--
作者：
James SJ;Shpyleva S;Melnyk S;Pavliv O;Pogribny IP
自闭症大脑中表观遗传改变的阐明有可能为这种疾病中异常基因表达的分子机制提供新的见解。鉴于强有力的证据表明，enrailed-2（EN-2）是一个发育表达的基因相关的小脑异常和自闭症，该候选基因的表观遗传学评价进行了26例和对照死后小脑样本。评估包括总体DNA甲基化、EN-2启动子甲基化、EN-2基因表达和EN-2蛋白水平。染色质免疫沉淀用于评估与基因下调相关的组蛋白H3赖氨酸27（H3 K27）和与基因激活相关的组蛋白H3赖氨酸4（H3 K4）的三甲基化状态。结果显示，一个不寻常的模式，全球和EN-2启动子区域DNA甲基化伴随着显着增加EN-2基因表达和蛋白水平。与EN-2过表达一致，EN-2启动子中的组蛋白H3 K27三甲基化标记在自闭症样品中相对于匹配的对照显著降低。支持组蛋白H3 K27三甲基化减少和EN-2基因表达增加之间的联系，组蛋白H3 K4三甲基化的平均水平在自闭症小脑样本中升高。总之，这些结果表明，正常的EN-2下调，信号浦肯野细胞成熟在产前晚期和出生后早期的发展可能没有发生在一些个体与自闭症和出生后持续EN-2过表达可能有助于自闭症小脑异常。
The elucidation of epigenetic alterations in the autism brain has potential to provide new insights into the molecular mechanisms underlying abnormal gene expression in this disorder. Given strong evidence that engrailed-2 (EN-2) is a developmentally expressed gene relevant to cerebellar abnormalities and autism, the epigenetic evaluation of this candidate gene was undertaken in 26 case and control post-mortem cerebellar samples. Assessments included global DNA methylation, EN-2 promoter methylation, EN-2 gene expression and EN-2 protein levels. Chromatin immunoprecipitation was used to evaluate trimethylation status of histone H3 lysine 27 (H3K27) associated with gene downregulation and histone H3 lysine 4 (H3K4) associated with gene activation. The results revealed an unusual pattern of global and EN-2 promoter region DNA hypermethylation accompanied by significant increases in EN-2 gene expression and protein levels. Consistent with EN-2 overexpression, histone H3K27 trimethylation mark in the EN-2 promoter was significantly decreased in the autism samples relative to matched controls. Supporting a link between reduced histone H3K27 trimethylation and increased EN-2 gene expression, the mean level of histone H3K4 trimethylation was elevated in the autism cerebellar samples. Together, these results suggest that the normal EN-2 downregulation that signals Purkinje cell maturation during late prenatal and early-postnatal development may not have occurred in some individuals with autism and that the postnatal persistence of EN-2 overexpression may contribute to autism cerebellar abnormalities.
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影响因子：
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作者：
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