Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases |
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| Authors: | 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 |
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| Institution: | 1. National Institute of Allergy and Infectious Diseases, , Bethesda, MD, USA;2. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, , New York, NY, USA;3. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, , New York, NY, USA;4. Merck Research Laboratories, Merck & Co., Inc., , Whitehouse Station, NJ, USA;5. Department of Integrative Biology and Physiology, University of California, , Los Angeles, CA, USA;6. Sage Bionetworks, , Seattle, WA, USA;7. National Heart, Lung and Blood Institute, , Bethesda, MD, USA;8. Department of Human Genetics, University of California, , Los Angeles, CA, USA;9. Icelandic Heart Association, , Kopavogur, Iceland;10. Faculty of Pharmaceutical Sciences, University of Iceland, , Reykjavik, Iceland |
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| 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). |
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| Keywords: | differential co‐expression dysregulatory gene networks epigenetic regulation of neural differentiation network alignment neurodegenerative diseases |
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