Department of Genetics and Genome Sciences, UConn Health, Farmington, CT 06030-6403.
Department of Molecular and Cellular Biology, University of Connecticut, Storrs, CT 06269-3197.
Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2181-2186. doi: 10.1073/pnas.1815279116. Epub 2019 Jan 23.
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function from the maternal allele of , a gene encoding an E3 ubiquitin ligase. is only expressed from the maternally inherited allele in mature human neurons due to tissue-specific genomic imprinting. Imprinted expression of is restricted to neurons by expression of () from the paternally inherited allele, which silences the paternal allele of in However, the mechanism restricting expression and imprinting to neurons is not understood. We used CRISPR/Cas9-mediated genome editing to functionally define a bipartite boundary element critical for neuron-specific expression of in humans. Removal of this element led to up-regulation of without repressing paternal However, increasing expression of in the absence of the boundary element resulted in full repression of paternal , demonstrating that imprinting requires both the loss of function from the boundary element as well as the up-regulation of These results suggest that manipulation of the competition between and may provide a potential therapeutic approach for AS.
天使综合征（AS）是一种严重的神经发育障碍，由编码 E3 泛素连接酶的基因的母本等位基因失去功能引起。由于组织特异性基因组印记，仅在成熟的人类神经元中从母本遗传等位基因表达 。通过从父本遗传等位基因表达 （）来限制印记表达和 到神经元，从而沉默 在 中的父本等位基因。然而，限制 表达和印记到神经元的机制尚不清楚。我们使用 CRISPR/Cas9 介导的基因组编辑来功能定义人类中 的神经元特异性表达的关键双分体边界元件。去除该元件会导致 的上调，而不会抑制父本 。然而，在不存在边界元件的情况下增加 的表达会导致完全抑制父本 ，表明 印记既需要从边界元件丧失功能，也需要上调 。这些结果表明，操纵 和 之间的竞争可能为 AS 提供一种潜在的治疗方法。
