Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases. Issue 7 (July 2014)

• Record Type: Journal Article
• Authors: Narayanan, Manikandan; Huynh, Jimmy L; Wang, Kai; Yang, Xia; Yoo, Seungyeul; McElwee, Joshua; Zhang, Bin; Zhang, Chunsheng; Lamb, John R; Xie, Tao; Suver, Christine; Molony, Cliona; Melquist, Stacey; Johnson, Andrew D; Fan, Guoping; Stone, David J; Schadt, Eric E; Casaccia, Patrizia; Emilsson, Valur; Zhu, Jun
• Is Part Of: Molecular systems biology. Volume 10:Issue 7(2014)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2014-07
• Subjects: Molecular biology -- Periodicals; Systems biology -- Periodicals; 572.8
• DOI: 10.15252/msb.20145304
• Languages: English
• ISSNs: 1744-4292

Abstract

<abstract abstract-type="main" id="msb145304-abs-0001"> <title>Abstract</title> <p>Using expression profiles from postmortem prefrontal cortex samples of 624 dementia patients and non‐demented controls, we investigated global disruptions in the co‐regulation of genes in two neurodegenerative diseases, late‐onset Alzheimer's disease (AD) and Huntington's disease (HD). We identified networks of differentially co‐expressed (DC) gene pairs that either gained or lost correlation in disease cases relative to the control group, with the former dominant for both AD and HD and both patterns replicating in independent human cohorts of AD and aging. When aligning networks of DC patterns and physical interactions, we identified a 242‐gene subnetwork enriched for independent AD/HD signatures. This subnetwork revealed a surprising dichotomy of gained/lost correlations among two inter‐connected processes, chromatin organization and neural differentiation, and included DNA methyltransferases, <italic>DNMT1</italic> and <italic>DNMT3A</italic>, of which we predicted the former but not latter as a key regulator. To validate the inter‐connection of these two processes and our key regulator prediction, we generated two brain‐specific knockout (KO) mice and show that <italic>Dnmt1 </italic>KO signature significantly overlaps with the subnetwork (<italic>P </italic>=<italic> </italic>3.1 × 10<sup>−12</sup>), while <italic>Dnmt3a </italic>KO signature does not (<italic>P</italic> = 0.017).</p> </abstract>