497A Poster - 06. Regulation of gene expression
Thursday April 07, 2:00 PM - 4:00 PM

Authors:
Joshua Marsh; Madeleine Mok; Rachael French

Affiliation: San Jose State University

Keywords:
j. epigenetics; k. developmental disorders

Ethanol is a teratogen. Developmental alcohol exposure (DAE) in humans leads to a Fetal Alcohol Spectrum Disorder (FASD). Individuals with FASD can exhibit a variety of deleterious phenotypes, including slow growth, metabolic changes, behavioral difficulties, and intellectual disabilities. Recent findings in mammals indicate that metabolic changes associated with DAE involve long-term changes in gene expression mediated by epigenetic effects.

We have established Drosophila as a model for FASD. Using this model, we have found that flies exposed to ethanol during larval stages display phenotypes similar to mammals exposed during fetal development, including developmental delay, reduced adult size, smaller brains, CNS dysfunction, reduced sensitivity to ethanol sedation, impaired insulin signaling and lipid metabolism, and reduced survival. Some of these phenotypes, including impaired lipid metabolism and sedation resistance, persist into adulthood. Consistent with this observation, we have shown that DAE causes long term changes in gene expression.

Ethanol exposure in adult flies alters the expression of histone modifying enzymes. We hypothesize that some of the long-term changes in phenotype and gene expression caused by DAE are due to epigenetic alterations in gene expression due to similar effects on the expression of histone modifiers. To test this hypothesis, we tested the DAE sensitivity of flies mutant for a variety of histone modifiers. In addition, we used qPCR to measure the expression of genes encoding histone modifiers in ethanol-reared larvae.

We will present data showing that mutations disrupting the histone modifiers Sirt1, Lid, dG9a, JHDM2, and NO66 result in changes in sensitivity to DAE. Additionally, DAE causes reduced expression of G9a, Sirt1, and Lid in larvae. Thus, DAE alters epigenetic regulation of gene expression, and it is likely that some DAE-induced phenotypes are due to these effects.

We will additionally present the results of experiments to test the effects of DAE on additional histone modifying enzymes, as well as the role of those proteins in sensitivity to developmental ethanol. In addition, we are testing whether persistent DAE-induced phenotypes are due to changes in epigenetic regulation of gene expression.