title: Assembly and interrogation of Alzheimer's disease genetic networks reveal novel regulators of progression.
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.
authors.affiliation: Taub Institute for Research on Alzheimer's Disease & the Aging Brain and the Department of Pathology & Cell Biology, Columbia University, New York, NY, 10032, United States of America.
authors.forename: Soline
authors.initials: S
authors.lastname: Aubry
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY, 10032, United States of America; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, 10032, United States of America; Department of Biological Sciences, Columbia University, New York, NY, 10027, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Shin
authors.affiliation: Taub Institute for Research on Alzheimer's Disease & the Aging Brain and the Department of Pathology & Cell Biology, Columbia University, New York, NY, 10032, United States of America.
authors.forename: John F
authors.initials: JF
authors.lastname: Crary
authors.affiliation: Taub Institute for Research on Alzheimer's Disease & the Aging Brain and the Department of Pathology & Cell Biology, Columbia University, New York, NY, 10032, United States of America.
authors.forename: Roger
authors.initials: R
authors.lastname: Lefort
authors.affiliation: Taub Institute for Research on Alzheimer's Disease & the Aging Brain and the Department of Pathology & Cell Biology, Columbia University, New York, NY, 10032, United States of America.
authors.forename: Yasir H
authors.initials: YH
authors.lastname: Qureshi
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY, 10032, United States of America; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, 10032, United States of America; Inserm Unit U981, Institut Gustave Roussy, 94805, Villejuif, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Lefebvre
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY, 10032, United States of America; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, 10032, United States of America; Department of Biological Sciences, Columbia University, New York, NY, 10027, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.affiliation: Taub Institute for Research on Alzheimer's Disease & the Aging Brain and the Department of Pathology & Cell Biology, Columbia University, New York, NY, 10032, United States of America.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Shelanski
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats
chemical_list: D009419:Nerve Tissue Proteins