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      The Plasticizer Bisphenol A Perturbs the Hepatic Epigenome: A Systems Level Analysis of the miRNome

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          Abstract

          Ubiquitous exposure to bisphenol A (BPA), an endocrine disruptor (ED), has raised concerns for both human and ecosystem health. Epigenetic factors, including microRNAs (miRNAs), are key regulators of gene expression during cancer. The effect of BPA exposure on the zebrafish epigenome remains poorly characterized. Zebrafish represents an excellent model to study cancer as the organism develops a disease that resembles human cancer. Using zebrafish as a systems toxicology model, we hypothesized that chronic BPA-exposure impacts the miRNome in adult zebrafish and establishes an epigenome more susceptible to cancer development. After a 3 week exposure to 100 nM BPA, RNA from the liver was extracted to perform high throughput mRNA and miRNA sequencing. Differential expression (DE) analyses comparing BPA-exposed to control specimens were performed using established bioinformatics pipelines. In the BPA-exposed liver, 6188 mRNAs and 15 miRNAs were differently expressed ( q ≤ 0.1). By analyzing human orthologs of the DE zebrafish genes, signatures associated with non-alcoholic fatty liver disease (NAFLD), oxidative phosphorylation, mitochondrial dysfunction and cell cycle were uncovered. Chronic exposure to BPA has a significant impact on the liver miRNome and transcriptome in adult zebrafish with the potential to cause adverse health outcomes including cancer.

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          Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.

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            Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals.

            Comprehensive identification of all functional elements encoded in the human genome is a fundamental need in biomedical research. Here, we present a comparative analysis of the human, mouse, rat and dog genomes to create a systematic catalogue of common regulatory motifs in promoters and 3' untranslated regions (3' UTRs). The promoter analysis yields 174 candidate motifs, including most previously known transcription-factor binding sites and 105 new motifs. The 3'-UTR analysis yields 106 motifs likely to be involved in post-transcriptional regulation. Nearly one-half are associated with microRNAs (miRNAs), leading to the discovery of many new miRNA genes and their likely target genes. Our results suggest that previous estimates of the number of human miRNA genes were low, and that miRNAs regulate at least 20% of human genes. The overall results provide a systematic view of gene regulation in the human, which will be refined as additional mammalian genomes become available.
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              Cell cycle proteins as promising targets in cancer therapy

              Cancer is characterized by uncontrolled tumour cell proliferation resulting from aberrant activity of various cell cycle proteins. Therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrate that some of these proteins are not essential for proliferation of non-transformed cells
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Genes (Basel)
                Genes (Basel)
                genes
                Genes
                MDPI
                2073-4425
                13 October 2017
                October 2017
                : 8
                : 10
                Affiliations
                [1 ]Division of Nephrology, Department of Medicine, Medical University of South Carolina (MUSC),Charleston, SC 29425, USA; renaudl@ 123456musc.edu
                [2 ]Laboratory for Marine Systems Biology, Hollings Marine Laboratory, Charleston, SC 29412, USA
                [3 ]Center for Genomic Medicine, Bioinformatics, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA; silveira@ 123456musc.edu (W.A.S.); hazards@ 123456musc.edu (E.S.H.); jondsimp@ 123456gmail.com (J.S.)
                [4 ]Library Science and Informatics, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA
                [5 ]Dipartimento di Scienze della Vita e dell’Ambiente, Università Politecnica delle Marche, 60131 Ancona, Italy; falcinelli.silvia@ 123456gmail.com (S.F.); o.carnevali@ 123456univpm.it (O.C.)
                [6 ]Department of Public Health Sciences, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA; chungd@ 123456musc.edu
                [7 ]Department of Medicine, University of California, La Jolla, CA 92093, USA
                Author notes
                [* ]Correspondence: hardiman@ 123456musc.edu ; Tel.: +1-843-792-0771
                Article
                genes-08-00269
                10.3390/genes8100269
                5664119
                29027980
                602b70b1-2764-4fa1-8949-49f2b1a3b3c6
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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