Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons.
Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons.
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15Q重复的重大转录变化，但没有安吉尔曼综合征删除干细胞衍生的神经元。
DOI：
10.1186/s13229-018-0191-y
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发表时间：
2018
期刊：
影响因子：
6.2
通讯作者：
Reiter LT
中科院分区：
文献类型：
--
作者：
Urraca N;Hope K;Victor AK;Belgard TG;Memon R;Goorha S;Valdez C;Tran QT;Sanchez S;Ramirez J;Donaldson M;Bridges D;Reiter LT
由于无法分析 Angelman (AS) 和重复 15q (Dup15q) 综合征受试者活神经元的基因表达，限制了我们在分子水平上对这些疾病的理解。在这里，我们使用来自 AS 缺失、15q 重复和神经典型对照受试者的牙髓干细胞 (DPSC) 进行全转录组分析。我们鉴定了 20 个 AS 神经元特有的基因、120 个 15q 重复特有的基因以及 3 个在 DPSC 神经元与对照组中差异表达的共享转录本。拷贝数与 15q11.2-q13.1 关键区域大多数基因的基因表达相关。与包含多个转录因子的对照相比，15q 重复神经元中差异表达的基因的三分之二被下调，而在 AS 中差异表达主要限于 15q 区域。在这里，我们发现 15q 重复的神经元中转录因子 FOXO1 和 HAND2 显着下调，但 AS 缺失受试者则不然，这表明转录调控的破坏可能是 Dup15q 综合征自闭症表型的驱动因素。下游分析显示 ASD 相关基因 EHPB2 和 RORA 下调，这两个基因均具有 FOXO1 结合位点。 Dup15q 皮质或特发性 ASD 皮质中上调的基因均与 Dup15q DPSC 衍生神经元中上调最多的基因显着重叠。发现 Dup15q 神经元中 HERC2 和 UBE3A 均显着增加，而 AS 缺失神经元中这两个基因显着减少，这可能解释了 AS 缺失类别和 AS 突变的 UBE3A 特定类别之间的差异，其中 HERC2 以正常水平表达。此外，我们还发现了 Dup15q 神经元中 FOXO1 调节转录物的富集，包括 ASD 相关基因 EHPB2 和 RORA，表明这种 ASD 综合征形式与特发性病例之间可能存在联系。本文的在线版本 (10.1186/s13229-018-0191-y) 包含补充材料，可供授权用户使用。
The inability to analyze gene expression in living neurons from Angelman (AS) and Duplication 15q (Dup15q) syndrome subjects has limited our understanding of these disorders at the molecular level. Here, we use dental pulp stem cells (DPSC) from AS deletion, 15q Duplication, and neurotypical control subjects for whole transcriptome analysis. We identified 20 genes unique to AS neurons, 120 genes unique to 15q duplication, and 3 shared transcripts that were differentially expressed in DPSC neurons vs controls. Copy number correlated with gene expression for most genes across the 15q11.2-q13.1 critical region. Two thirds of the genes differentially expressed in 15q duplication neurons were downregulated compared to controls including several transcription factors, while in AS differential expression was restricted primarily to the 15q region. Here, we show significant downregulation of the transcription factors FOXO1 and HAND2 in neurons from 15q duplication, but not AS deletion subjects suggesting that disruptions in transcriptional regulation may be a driving factor in the autism phenotype in Dup15q syndrome. Downstream analysis revealed downregulation of the ASD associated genes EHPB2 and RORA, both genes with FOXO1 binding sites. Genes upregulated in either Dup15q cortex or idiopathic ASD cortex both overlapped significantly with the most upregulated genes in Dup15q DPSC-derived neurons. Finding a significant increase in both HERC2 and UBE3A in Dup15q neurons and significant decrease in these two genes in AS deletion neurons may explain differences between AS deletion class and UBE3A specific classes of AS mutation where HERC2 is expressed at normal levels. Also, we identified an enrichment for FOXO1-regulated transcripts in Dup15q neurons including ASD-associated genes EHPB2 and RORA indicating a possible connection between this syndromic form of ASD and idiopathic cases. The online version of this article (10.1186/s13229-018-0191-y) contains supplementary material, which is available to authorized users.
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影响因子：
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影响因子：
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Griesi-Oliveira, K.;Acab, A.;Gupta, A. R.;Sunaga, D. Y.;Chailangkarn, T.;Nicol, X.;Nunez, Y.;Walker, M. F.;Murdoch, J. D.;Sanders, S. J.;Fernandez, T. V.;Ji, W.;Lifton, R. P.;Vadasz, E.;Dietrich, A.;Pradhan, D.;Song, H.;Ming, G-I;Gu, X.;Haddad, G.;Marchetto, M. C. N.;Spitzer, N.;Passos-Bueno, M. R.;State, M. W.;Muotri, A. R.
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