Assembly and interrogation of Alzheimer's disease genetic networks reveal novel regulators of progression

PloS One
Soline AubryMichael L Shelanski

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 ...Continue Reading

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Datasets Mentioned

BETA
GSE5281

Methods Mentioned

BETA
laser-capture microdissection
acetylation
ubiquitination
acetylations
Protein Assay
electrophoresis

Software Mentioned

Master Regulator INference algorithm ( MARINa )
Master Regulator Inference analysis ( MARINa )
GSEA
gcrma
Axiovision
Interactome
Array
BRB
Master Regulator Analysis
ARACNe

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