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Epigenetic Regulation of Dopamine Transporter Expression

by
Ashley L. Green
B.S., Rutgers University 2008

Thesis Advisor: Jason R. Richardson, M.S., Ph.D.
Graduate Program in Toxicology

EOHSI - Conference Room C
Piscataway

Wednesday, September 24, 2014
9:00 a.m.


Abstract

The dopamine transporter (DAT) is responsible for determining the duration and intensity of dopaminergic signaling by removing dopamine from the nerve synapse. Consequently, alterations in dopaminergic transmission and DAT expression stand to adversely affect neurological activities. DAT expression can be altered by a number of xenobiotics, including pesticides and pharmacological agents. Therefore, determination of the mechanisms by which DAT expression is regulated may provide insight into the actions of these compounds on the nervous system. Using in silico analyses, we identified regions within the DAT promoter, which may contribute to its epigenetic regulation at the mRNA level. Next, we used in vitro and in vivo models to determine the relative roles of DNA methylation and histone acetylation in the regulation of DAT mRNA expression. In vitro, DNMT and HDAC inhibitors caused a 2- and 10- fold increase in DAT mRNA expression, respectively. The effect of HDAC inhibition on DAT expression was confirmed by chromatin immunoprecipitiation (ChIP), which identified enrichment of H3K9/K14Ac within the DAT promoter. In vivo, increased DAT mRNA during postnatal development and following developmental exposure to the pesticide deltamethrin showed similar promoter enrichment of H3K9/K14Ac and the essential dopaminergic transcription factor Pitx3. Taken together, these data are the first to identify epigenetic regulators of DAT expression. In turn, this information provides insight into mechanisms by which DAT expression may be manipulated in vivo, which may provide a means to normalize dopaminergic function in diseases in which DAT is disrupted or altered following exposure to drugs and toxicants.


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