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

被引：147

作者：

Narayanan, Manikandan ^{[1
]}

Huynh, Jimmy L. ^{[2
,3
]}

Wang, Kai ^{[4
]}

Yang, Xia ^{[5
]}

Yoo, Seungyeul ^{[3
]}

McElwee, Joshua ^{[4
]}

Zhang, Bin ^{[3
]}

Zhang, Chunsheng ^{[4
]}

Lamb, John R. ^{[4
]}

Xie, Tao ^{[4
]}

Suver, Christine ^{[6
]}

Molony, Cliona ^{[4
]}

Melquist, Stacey ^{[4
]}

Johnson, Andrew D. ^{[7
]}

Fan, Guoping ^{[8
]}

Stone, David J. ^{[4
]}

Schadt, Eric E. ^{[3
]}

Casaccia, Patrizia ^{[2
,3
]}

Emilsson, Valur ^{[9
,10
]}

Zhu, Jun ^{[3
]}

机构：

[1] NIAID, Bethesda, MD 20892 USA

[2] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA

[3] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[4] Merck & Co Inc, Merck Res Labs, Whitehouse Stn, NJ USA

[5] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA USA

[6] Sage Bionetworks, Seattle, WA USA

[7] NHLBI, Bethesda, MD 20892 USA

[8] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA

[9] Iceland Heart Assoc, Kopavogur, Iceland

[10] Univ Iceland, Fac Pharmaceut Sci, Reykjavik, Iceland

来源：

MOLECULAR SYSTEMS BIOLOGY | 2014年 / 10卷 / 07期

关键词：

differential co-expression; dysregulatory gene networks; epigenetic regulation of neural differentiation; network alignment; neurodegenerative diseases; ALZHEIMERS-DISEASE; DNA METHYLATION; GENE-EXPRESSION; EPIGENETIC MECHANISMS; DIFFERENTIATION; TRANSCRIPTION; NEURONS; PROTEIN; OLIGODENDROCYTES; ASTROCYTES;

D O I：

10.15252/msb.20145304

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 methyl-transferases, 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 x 10(-12)), while Dnmt3a KO signature does not (P = 0.017).

引用

页数：16

共 73 条

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