Alcoholism and fetal alcohol syndrome are the result of the complex interaction of multiple genetic and environmental factors. Recently, it has become apparent that in addition to genetic and environmental factors, epigenetic mechanisms play crucial roles in the etiology of a large number of diseases such as cancer and schizophrenia. Furthermore, developmental abnormalities are known to be associated with aberrant epigenetic changes in DNA and chromatin. Covalent histone modifications and DNA cytosine methylation, particularly in gene promoter regions, are key epigenetic modifications that control chromatin structure and gene expression. Alcohol and its metabolite acetic acid have strong propensity to deregulate methylation donor by inhibiting a key folate-methionine metabolism pathway leading to altered methylation. Thus, fetal development actively engaged in DNA transcription and cell cycling would be a prime target by alcoholinduced epigenetic abnormalities. This proposal will determine if alcohol cause aberrant epigenetic changes in the fetus, and if the alcohol-induced epigenetic abnormalities lead to fetal alcohol syndrome. Our preliminary data indicates that prenatal alcohol exposure causes decreased multiple linker and core histone genes expression, changes histone methylation, and altered gene expression leading to neural specification. In this proposal, we will study alcohol-mediated epigenetic changes in developing embryos. The alcohol exposure level will be carefully controlled, and our analysis will be able to distinguish maternal imprinting from epigenetic effects due to direct alcohol exposure. We will use a C57BL//6J mice whole embryonic culture model, differential methylation hybridization, and novel ChlP-chip technology to determine genome wide epigenetic changes induced by alcohol. Second, we will identify cohort of genes with promoter methylation and transcriptional alterations, confirm the findings using standard RT-PCR / western blot, and determine their functional pathways. Furthermore, the biological significance of the confirmed key genes will be determined using pharmacological inhibitors of DNA methylation and histone acetylation or genetic manipulation, along with phenotypic analysis. The effect of these epigenetic key genes will be confirmed in the in vivo model exposed to alcohol vapor chamber with alcohol exposure pattern and paradigms similar to the whole embryonic culture. ? ? ?
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