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...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2014-07-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.15252/msb.20145304 |
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| author | Manikandan Narayanan Jimmy L Huynh Kai Wang Xia Yang Seungyeul Yoo Joshua McElwee Bin Zhang Chunsheng Zhang John R Lamb Tao Xie Christine Suver Cliona Molony Stacey Melquist Andrew D Johnson Guoping Fan David J Stone Eric E Schadt Patrizia Casaccia Valur Emilsson Jun Zhu |
| author_facet | Manikandan Narayanan Jimmy L Huynh Kai Wang Xia Yang Seungyeul Yoo Joshua McElwee Bin Zhang Chunsheng Zhang John R Lamb Tao Xie Christine Suver Cliona Molony Stacey Melquist Andrew D Johnson Guoping Fan David J Stone Eric E Schadt Patrizia Casaccia Valur Emilsson Jun Zhu |
| author_sort | Manikandan Narayanan |
| collection | DOAJ |
| description | 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). |
| format | Article |
| id | doaj-art-ad673633ea9c41b9b14d2c564cc9243f |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2014-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-ad673633ea9c41b9b14d2c564cc9243f2025-08-20T04:03:12ZengSpringer NatureMolecular Systems Biology1744-42922014-07-0110711610.15252/msb.20145304Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseasesManikandan Narayanan0Jimmy L Huynh1Kai Wang2Xia Yang3Seungyeul Yoo4Joshua McElwee5Bin Zhang6Chunsheng Zhang7John R Lamb8Tao Xie9Christine Suver10Cliona Molony11Stacey Melquist12Andrew D Johnson13Guoping Fan14David J Stone15Eric E Schadt16Patrizia Casaccia17Valur Emilsson18Jun Zhu19National Institute of Allergy and Infectious DiseasesDepartment of Neuroscience, Icahn School of Medicine at Mount SinaiMerck Research Laboratories, Merck & Co., Inc.Department of Integrative Biology and Physiology, University of CaliforniaDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiMerck Research Laboratories, Merck & Co., Inc.Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiMerck Research Laboratories, Merck & Co., Inc.Merck Research Laboratories, Merck & Co., Inc.Merck Research Laboratories, Merck & Co., Inc.Sage BionetworksMerck Research Laboratories, Merck & Co., Inc.Merck Research Laboratories, Merck & Co., Inc.National Heart, Lung and Blood InstituteDepartment of Human Genetics, University of CaliforniaMerck Research Laboratories, Merck & Co., Inc.Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Neuroscience, Icahn School of Medicine at Mount SinaiIcelandic Heart AssociationDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiAbstract 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).https://doi.org/10.15252/msb.20145304differential co‐expressiondysregulatory gene networksepigenetic regulation of neural differentiationnetwork alignmentneurodegenerative diseases |
| spellingShingle | Manikandan Narayanan Jimmy L Huynh Kai Wang Xia Yang Seungyeul Yoo Joshua McElwee Bin Zhang Chunsheng Zhang John R Lamb Tao Xie Christine Suver Cliona Molony Stacey Melquist Andrew D Johnson Guoping Fan David J Stone Eric E Schadt Patrizia Casaccia Valur Emilsson Jun Zhu Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases Molecular Systems Biology differential co‐expression dysregulatory gene networks epigenetic regulation of neural differentiation network alignment neurodegenerative diseases |
| title | Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases |
| title_full | Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases |
| title_fullStr | Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases |
| title_full_unstemmed | Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases |
| title_short | Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases |
| title_sort | common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases |
| topic | differential co‐expression dysregulatory gene networks epigenetic regulation of neural differentiation network alignment neurodegenerative diseases |
| url | https://doi.org/10.15252/msb.20145304 |
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