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      Differential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in major psychosis

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          Abstract

          Impaired neuronal processes, including dopamine imbalance, are central to the pathogenesis of major psychosis, but the molecular origins are unclear. Here we perform a multi-omics study of neurons isolated from the prefrontal cortex in schizophrenia and bipolar disorder (n = 55 cases and 27 controls). DNA methylation, transcriptomic, and genetic-epigenetic interactions in major psychosis converged on pathways of neurodevelopment, synaptic activity, and immune functions. We observe prominent hypomethylation of an enhancer within the insulin-like growth factor 2 ( IGF2) gene in major psychosis neurons. Chromatin conformation analysis revealed that this enhancer targets the nearby tyrosine hydroxylase ( TH) gene responsible for dopamine synthesis. In patients, we find hypomethylation of the IGF2 enhancer is associated with increased TH protein levels. In mice, Igf2 enhancer deletion disrupts the levels of TH protein and striatal dopamine, and induces transcriptional and proteomic abnormalities affecting neuronal structure and signaling. Our data suggests that epigenetic activation of the enhancer at IGF2 may enhance dopamine synthesis associated with major psychosis.

          Abstract

          Dopamine dysregulation is centrally linked to major psychosis. Here, the authors characterise the hypomethylation of an enhancer within the insulin-like growth factor 2 gene in neurons of patients with major psychosis and provide evidence that this enhancer targets the tyrosine hydroxylase gene, responsible for dopamine synthesis.

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          Most cited references44

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          Gene Ontology: tool for the unification of biology

          Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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            The PANTHER database of protein families, subfamilies, functions and pathways

            PANTHER is a large collection of protein families that have been subdivided into functionally related subfamilies, using human expertise. These subfamilies model the divergence of specific functions within protein families, allowing more accurate association with function (ontology terms and pathways), as well as inference of amino acids important for functional specificity. Hidden Markov models (HMMs) are built for each family and subfamily for classifying additional protein sequences. The latest version, 5.0, contains 6683 protein families, divided into 31 705 subfamilies, covering ∼90% of mammalian protein-coding genes. PANTHER 5.0 includes a number of significant improvements over previous versions, most notably (i) representation of pathways (primarily signaling pathways) and association with subfamilies and individual protein sequences; (ii) an improved methodology for defining the PANTHER families and subfamilies, and for building the HMMs; (iii) resources for scoring sequences against PANTHER HMMs both over the web and locally; and (iv) a number of new web resources to facilitate analysis of large gene lists, including data generated from high-throughput expression experiments. Efforts are underway to add PANTHER to the InterPro suite of databases, and to make PANTHER consistent with the PIRSF database. PANTHER is now publicly available without restriction at http://panther.appliedbiosystems.com.
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              Rectangular Confidence Regions for the Means of Multivariate Normal Distributions

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                Author and article information

                Contributors
                shraddha.pai@utoronto.ca
                viviane.labrie@vai.org
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                3 May 2019
                3 May 2019
                2019
                : 10
                : 2046
                Affiliations
                [1 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, The Donnelly Centre, University of Toronto, ; Toronto, M5S 3E1 ON Canada
                [2 ]ISNI 0000 0000 8793 5925, GRID grid.155956.b, The Centre for Addiction and Mental Health, ; Toronto, M5T 1R8 ON Canada
                [3 ]ISNI 0000 0004 0406 2057, GRID grid.251017.0, Center for Neurodegenerative Science, Van Andel Research Institute, ; Grand Rapids, 49503 MI USA
                [4 ]ISNI 0000 0000 8793 5925, GRID grid.155956.b, Krembil Family Epigenetics Laboratory, , Centre for Addiction and Mental Health, ; Toronto, M5T 1R8 ON Canada
                [5 ]ISNI 0000 0004 0406 2057, GRID grid.251017.0, Center for Epigenetics, Van Andel Research Institute, ; Grand Rapids, 49503 MI USA
                [6 ]ISNI 0000 0001 2243 2806, GRID grid.6441.7, Institute of Biotechnology, Life Sciences Center, Vilnius University, ; LT-10257 Vilnius, Lithuania
                [7 ]ISNI 0000 0001 2150 1785, GRID grid.17088.36, Division of Psychiatry and Behavioral Medicine, , College of Human Medicine, Michigan State University, ; Grand Rapids, 49503 MI USA
                Author information
                http://orcid.org/0000-0002-8043-8517
                Article
                9786
                10.1038/s41467-019-09786-7
                6499808
                31053723
                8d2ed7ee-089d-4004-aa07-fe597ca69db8
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 30 April 2018
                : 27 March 2019
                Categories
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                Custom metadata
                © The Author(s) 2019

                Uncategorized
                epigenomics,gene regulation,chromatin structure,psychosis,genetics of the nervous system

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