Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases

Mol Syst Biol. 2014 Jul 30;10(7):743. doi: 10.15252/msb.20145304.

Abstract

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, DNMT1 and DNMT3A, 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).

Keywords: differential co‐expression; dysregulatory gene networks; epigenetic regulation of neural differentiation; network alignment; neurodegenerative diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Animals
  • Autopsy
  • Case-Control Studies
  • Chromatin / metabolism
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • Dementia / pathology
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Regulatory Networks*
  • Humans
  • Huntington Disease / genetics*
  • Huntington Disease / pathology
  • Mice
  • Mice, Knockout
  • Prefrontal Cortex / metabolism*
  • Prefrontal Cortex / pathology
  • Reproducibility of Results

Substances

  • Chromatin
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • DNMT1 protein, human
  • Dnmt1 protein, mouse