Laboratory for Neurobiology of Psychiatric Disorders, Sagol Department of Neurobiology, University of Haifa, Haifa 3498838, Israel.
Int J Mol Sci. 2022 Aug 15;23(16):9139. doi: 10.3390/ijms23169139.
Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of function of the E3-ligase UBE3A. Despite multiple studies, AS pathophysiology is still obscure and has mostly been explored in rodent models of the disease. In recent years, a growing body of studies has utilized omics datasets in the attempt to focus research regarding the pathophysiology of AS. Here, for the first time, we utilized a multi-omics approach at the epigenomic level and the transcriptome level, for human-derived neurons. Using publicly available datasets for DNA methylation and gene expression, we found genome regions in proximity to gene promoters and intersecting with gene-body regions that were differentially methylated and differentially expressed in AS. We found that overall, the genome in AS postmortem brain tissue was hypo-methylated compared to healthy controls. We also found more upregulated genes than downregulated genes in AS. Many of these dysregulated genes in neurons obtained from AS patients are known to be critical for neuronal development and synaptic functioning. Taken together, our results suggest a list of dysregulated genes that may be involved in AS development and its pathological features. Moreover, these genes might also have a role in neurodevelopmental disorders similar to AS.
天使综合征（AS）是一种神经发育障碍，由 E3 连接酶 UBE3A 的功能丧失引起。尽管进行了多项研究，但 AS 的病理生理学仍然不清楚，并且主要在疾病的啮齿动物模型中进行了探索。近年来，越来越多的研究利用组学数据集试图关注 AS 病理生理学的研究。在这里，我们首次在人类来源的神经元中利用表观基因组和转录组水平的多组学方法。使用公开的 DNA 甲基化和基因表达数据集，我们发现了与基因启动子附近且与基因体区域相交的基因组区域，这些区域在 AS 中表现出差异甲基化和差异表达。我们发现，与健康对照组相比，AS 死后脑组织的整个基因组呈低甲基化状态。我们还发现 AS 中上调的基因多于下调的基因。从 AS 患者中获得的神经元中的许多这些失调基因已知对神经元发育和突触功能至关重要。总之，我们的结果表明了一组可能参与 AS 发展及其病理特征的失调基因。此外，这些基因在类似于 AS 的神经发育障碍中也可能具有作用。
