Faculty Bibliography

Ethanol administration to neonatal animals leads to a significant loss of cells in various regions of the brain, including the hippocampus, and impairs long-term potentiation (LTP), which is a physiological correlate of memory. Chromatin remodeling by histone modification plays an important role in several aspects of long-term cellular plasticity, including neuronal differentiation, learning and memory, drug addiction and neurodegeneration. Dimethylation of histone-3 Lys 9 (H3K9me2) correlates with transcriptional silencing, and trimethylation of histone-3 Lys 4 (H3K4me3) is linked to active transcription. Recently, histone (H3) methylation was implicated in the regulation of chromatin remodeling in the nervous system and the process of long-term memory storage. Postnatal ethanol-induces neurodegeneration in rodents, although the molecular mechanisms by which this occurs and physiological consequences are largely limited. In the current study, we show the participation of specific histone methyl transferase mediated dimethylation of histone-3 at lysine 4 in neonatal one or more brain regions. The results suggest that postnatal ethanol-induces robust apoptotic neurodegeneration as indicated by enhanced active caspase-3 immunoreactivity as well as electron microscope ultra structural features in hippocampus, cortex and cerebellum. These conditions resulted in enhanced expression of H3K9 specific histone methyl transferase (G9a/ b) mRNA and protein in a dose and time dependent manner. This is followed by enhanced dimethylation of H3K9 in hippocampus, cortex and cerebellum, although dual immunofluorescence histochemistry reveals that active caspase-3 positive neurons show diminishing immunoreactivity against H3K9me2. The results collectively suggest that developmental ethanol not only induces neurodegeneration but also enhances H3K9 dimethylation through histone methyl transferase, G9a/b. The current finding highlights the histone methylation mediated epigenetic modification as a valuable target in the therapy for fetal alcohol spectrum disorders