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https://doi.org/10.1371/journal.pone.0120352
Title: | Assembly and interrogation of Alzheimer's disease genetic networks reveal novel regulators of progression | Authors: | Aubry S. Shin W. Crary J.F. Lefort R. Qureshi Y.H. Lefebvre C. Califano A. Shelanski M.L. |
Keywords: | E1A associated p300 protein protein ZMYM3 transcription factor YY1 unclassified drug zinc finger protein nerve protein acetylation Alzheimer disease animal cell Article controlled study disease course female gene expression profiling gene regulatory network genetic algorithm genetic identification hippocampus human human cell male nonhuman phylogenetic tree rat reverse engineering systems biology transcription regulation validation study visual cortex Alzheimer disease animal gene expression regulation genetics metabolism pathology Alzheimer Disease Animals Gene Expression Regulation Gene Regulatory Networks Humans Nerve Tissue Proteins Rats |
Issue Date: | 2015 | Citation: | Aubry S., Shin W., Crary J.F., Lefort R., Qureshi Y.H., Lefebvre C., Califano A., Shelanski M.L. (2015). Assembly and interrogation of Alzheimer's disease genetic networks reveal novel regulators of progression. PLoS ONE 10 (3) : e0120352. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0120352 | Rights: | Attribution 4.0 International | Abstract: | 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. © 2015 Aubry et al. | Source Title: | PLoS ONE | URI: | https://scholarbank.nus.edu.sg/handle/10635/161741 | ISSN: | 19326203 | DOI: | 10.1371/journal.pone.0120352 | Rights: | Attribution 4.0 International |
Appears in Collections: | Elements Staff Publications |
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