Open AccessCommon dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases
Author(s) -
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
Publication year - 2014
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.15252/msb.20145304
Subject(s) - biology , prefrontal cortex , regulator , neuroscience , subnetwork , disease , chromatin , genetics , gene , cognition , medicine , computer security , computer science
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, DNMT 1 and DNMT 3A , 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 Dnmt1 KO signature significantly overlaps with the subnetwork ( P = 3.1 × 10 −12 ), while Dnmt3a KO signature does not ( P = 0.017).