Brain in situ hybridization maps as a source for reverse-engineering transcriptional regulatory networks: Alzheimer's disease insights
Brain in situ hybridization maps as a source for reverse-engineering transcriptional regulatory networks: Alzheimer's disease insights
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DOI：
10.1016/j.gene.2016.03.045
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发表时间：
2016-07-15
期刊：
影响因子：
3.5
通讯作者：
Taylor, Ronald C.
中科院分区：
文献类型：
--
作者：
Acquaah-Mensah, George K.;Taylor, Ronald C.
微阵列数据已成为鉴定基因间转录调控关系的宝贵资源。例如，脑区域特异性转录调控事件具有提供阿尔茨海默病（AD）病因学见解的潜力。然而，通常缺乏通过微阵列或其他高通量手段获得的合适的脑区域特异性表达数据。艾伦脑图谱原位杂交（ISH）数据集（Jones等人，2009）代表了用于此类目的的高通量脑区域特异性基因表达数据的潜在有价值的替代来源。本研究提取了艾伦脑图谱小鼠海马区的ISH数据，重点研究了508个与神经退行性变相关的基因。使用三种高性能网络推理算法学习转录调控网络。在小鼠全脑微阵列基因表达相关性构建的网络中，仅发现了基于脑区域特异性ISH数据反向工程的网络中17%的调控边缘，从而显示了脑亚区域内基因表达的特异性。此外，ISH数据为基础的网络被用来确定指导性的转录调控关系。Ncor2、Sp3和Usf2形成独特的三方调控基序，可能影响记忆形成途径。Nfe211、Egrl和Usf2出现在参与AD的基因（例如Dhcr24、Aplp2、Tal、Pdrxl、Vdacl和Syn2）的调节子中。此外，Nfe211、Egrl和Usf 2对饮食因素敏感，并且可能是饮食影响与AD病因学中的基因之间的联系。因此，这种利用大脑区域特异性ISH数据的方法代表了一个难得的机会，可以为AD等疾病收集独特的病因学见解。(C)2016爱思唯尔B.V.保留所有权利。
Microarray data have been a valuable resource for identifying transcriptional regulatory relationships among genes. As an example, brain region-specific transcriptional regulatory events have the potential of providing etiological insights into Alzheimer Disease (AD). However, there is often a paucity of suitable brain-region specific expression data obtained via microarrays or other high throughput means. The Allen Brain Atlas in situ hybridization (ISH) data sets (Jones et al., 2009) represent a potentially valuable alternative source of high-throughput brain region-specific gene expression data for such purposes. In this study, Allen Brain Atlas mouse ISH data in the hippocampal fields were extracted, focusing on 508 genes relevant to neurodegeneration. Transcriptional regulatory networks were learned using three high-performing network inference algorithms. Only 17% of regulatory edges from a network reverse-engineered based on brain region-specific ISH data were also found in a network constructed upon gene expression correlations in mouse whole brain microarrays, thus showing the specificity of gene expression within brain sub-regions. Furthermore, the ISH data-based networks were used to identify instructive transcriptional regulatory relationships. Ncor2, Sp3 and Usf2 form a unique three-party regulatory motif, potentially affecting memory formation pathways. Nfe211, Egrl and Usf2 emerge among regulators of genes involved in AD (e.g. Dhcr24, Aplp2, Tial, Pdrx1, Vdacl, and Syn2). Further, Nfe211, Egrl and Usf2 are sensitive to dietary factors and could be among links between dietary influences and genes in the AD etiology. Thus, this approach of harnessing brain region-specific ISH data represents a rare opportunity for gleaning unique etiological insights for diseases such as AD. (C) 2016 Elsevier B.V. All rights reserved.