title: Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases.
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).
authors: National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA manikandan.narayanan@nih.gov jun.zhu@mssm.edu.
authors: Manikandan
authors: M
authors: Narayanan
authors: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Jimmy L
authors: JL
authors: Huynh
authors: Merck Research Laboratories Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors: Kai
authors: K
authors: Wang
authors: Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA.
authors: Xia
authors: X
authors: Yang
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Seungyeul
authors: S
authors: Yoo
authors: Merck Research Laboratories Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors: Joshua
authors: J
authors: McElwee
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Bin
authors: B
authors: Zhang
authors: Merck Research Laboratories Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors: Chunsheng
authors: C
authors: Zhang
authors: Merck Research Laboratories Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors: John R
authors: JR
authors: Lamb
authors: Merck Research Laboratories Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors: Tao
authors: T
authors: Xie
authors: Sage Bionetworks, Seattle, WA, USA.
authors: Christine
authors: C
authors: Suver
authors: Merck Research Laboratories Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors: Cliona
authors: C
authors: Molony
authors: Merck Research Laboratories Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors: Stacey
authors: S
authors: Melquist
authors: National Heart, Lung and Blood Institute, Bethesda, MD, USA.
authors: Andrew D
authors: AD
authors: Johnson
authors: Department of Human Genetics, University of California, Los Angeles, CA, USA.
authors: Guoping
authors: G
authors: Fan
authors: Merck Research Laboratories Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors: David J
authors: DJ
authors: Stone
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Eric E
authors: EE
authors: Schadt
authors: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Patrizia
authors: P
authors: Casaccia
authors: Icelandic Heart Association, Kopavogur, Iceland Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland.
authors: Valur
authors: V
authors: Emilsson
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA manikandan.narayanan@nih.gov jun.zhu@mssm.edu.
authors: Jun
authors: J
authors: Zhu
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001344:Autopsy; D016022:Case-Control Studies; D002843:Chromatin / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D003704:Dementia / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D015203:Reproducibility of Results
chemical_list: D002843:Chromatin; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse
keywords: differential co‐expression; dysregulatory gene networks; epigenetic regulation of neural differentiation; network alignment; neurodegenerative diseases