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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2019.01099

Epigenetic Regulation of the Ontogenic Expression of the Dopamine Transporter

Ashley L. Green1,  Aseel Eid2, Le Zhan3,  Helmut Zarbl1, Grace L. Guo3, 4 and  Jason R. Richardson1, 5*
  • 1Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, United States
  • 2Department of Environmental Health Sciences, Robert Stempel College of Public Health & Social Work, Florida International University, United States
  • 3Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, United States
  • 4Department of Environmental Health Sciences and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, United States
  • 5Department of Environmental Health Sciences, Robert Stempel College of Public Health & Social Work, Florida International University, United States

The dopamine transporter (DAT) is a plasma membrane transport protein responsible for regulating the duration and intensity of dopaminergic signaling. Altered expression of DAT is linked to neurodevelopmental disorders, including attention deficit hyperactivity disorder and autism spectrum disorder, and is shown to contribute to the response of psychotropic drugs and neurotoxicants. Although the postnatal levels of DAT have been characterized, there are few data regarding the mechanisms that regulate postnatal DAT expression. Here, we examine the ontogeny of DAT mRNA from postnatal days 0 to 182 in the rat brain and define a role for epigenetic mechanisms regulating DAT expression. DAT mRNA and protein significantly increased between PND 0 and 6 months in rat midbrain and striatum, respectively. The epigenetic modifiers Dnmt1, Dnmt3a, Dnmt3b and Hdac2 demonstrated age associated decreases in mRNA expression whereas Hdac5 and Hdac8 showed increased mRNA expression with age. Chromatin immunoprecipitation studies revealed increased protein enrichment of acetylated histone 3 at lysines 9 and 14 and the dopaminergic transcription factors Nurr1 and Pitx3 within the DAT promoter in an age-related manner. Together these studies provide evidence for the role of epigenetic modifications in the regulation of DAT during development. The identification of these mechanisms may contribute to potential therapeutic interventions aimed at neurodevelopmental disorders of the dopaminergic system.

Keywords: Dopamine transporter (DAT, Ontogeny, epigenetics, histone modification, Nurr1

Received: 26 Jun 2019; Accepted: 11 Oct 2019.

Copyright: © 2019 Green, Eid, Zhan, Zarbl, Guo and Richardson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Jason R. Richardson, Robert Stempel College of Public Health & Social Work, Florida International University, Department of Environmental Health Sciences, Miami, 33199, Florida, United States, jarichar@fiu.edu