Assembly and Interrogation of Alzheimer's Disease Genetic Networks Reveal Novel Regulators of Progression
Assembly and Interrogation of Alzheimer's Disease Genetic Networks Reveal Novel Regulators of Progression
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DOI：
10.1371/journal.pone.0120352
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发表时间：
2015-03-17
期刊：
影响因子：
3.7
通讯作者：
Shelanski, Michael L.
中科院分区：
文献类型：
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作者：
Aubry, Soline;Shin, William;Shelanski, Michael L.
阿尔茨海默病（AD）是一种复杂的多因素疾病，其发病机制尚不清楚。因此，我们对这种疾病的理解将受益于一种解决这种复杂性的方法，即通过阐明阿尔茨海默病患者神经室中跨越不同大脑区域的失调调节网络。在这里，我们使用系统生物学（SB）方法，该方法在癌症相关表型的解剖中非常成功，对人类神经元细胞的转录调控层进行逆向工程，并对其进行询问，以推断负责疾病进展的候选主调控层（MRs）。使用精确细胞网络重建算法（ARACNe）对激光捕获的AD和对照受试者神经元的基因表达谱进行分析，得出了一个由488,353个转录因子/靶标相互作用组成的相互作用组。使用主调控推断算法（MARINa）对这一相互作用组进行了分析，确定了一组无偏倚的候选MRs，这些候选MRs与阿尔茨海默病进展的转录特征有因果关系。尸检来源的人脑组织的实验分析表明，与对照组相比，三种候选MRs （YY1， p300和ZMYM3）在AD大脑中确实在生化和组织病理学上失调。我们的研究结果还暗示了在神经退行性过程中p53和乙酰化稳态的丧失。该研究表明，一种综合的SB方法可以应用于AD和其他神经退行性疾病，并为疾病进展提供重要的新见解。
Alzheimer's disease (AD) is a complex multifactorial disorder with poorly characterized pathogenesis. Our understanding of this disease would thus benefit from an approach that addresses this complexity by elucidating the regulatory networks that are dysregulated in the neural compartment of AD patients, across distinct brain regions. Here, we use a Systems Biology (SB) approach, which has been highly successful in the dissection of cancer related phenotypes, to reverse engineer the transcriptional regulation layer of human neuronal cells and interrogate it to infer candidate Master Regulators (MRs) responsible for disease progression. Analysis of gene expression profiles from laser-captured neurons from AD and controls subjects, using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe), yielded an interactome consisting of 488,353 transcription-factor/target interactions. Interrogation of this interactome, using the Master Regulator INference algorithm (MARINa), identified an unbiased set of candidate MRs causally responsible for regulating the transcriptional signature of AD progression. Experimental assays in autopsy-derived human brain tissue showed that three of the top candidate MRs (YY1, p300 and ZMYM3) are indeed biochemically and histopathologically dysregulated in AD brains compared to controls. Our results additionally implicate p53 and loss of acetylation homeostasis in the neurodegenerative process. This study suggests that an integrative, SB approach can be applied to AD and other neurodegenerative diseases, and provide significant novel insight on the disease progression.