Angelman syndrome (AS) is a devastating disorder characterized by severe intellectual disability, absence of speech, abnormal gait, seizures, and inappropriate laughter. Loss of function or loss of expression of the maternal, but not paternal, UBE3A allele results in AS due to genomic imprinting of the gene in the brain. The mechanisms regulating genomic imprinting of UBE3A remain poorly understood. To address these important questions, our laboratory has initiated a number of molecular, epigenetic and genetic studies to identify factors regulating genomic imprinting of Ube3a in the brain. In our preliminary studies, we have found that Ube3a is expressed from both paternal and maternal alleles in neural stem cells (NSC) within the hippocampus of mice. Differentiation of these stem cells leads to repression of the paternal allele in neurons, but not in astrocytes. In specific aim 1, we will utilize RNA interference technology to identify epigenetic modifiers initiating and maintaining repression of the paternal Ube3a allele in neurons. Results from this study will provide valuable insight into the fundamental mechanisms regulating genomic imprinting of Ube3a in the brain and may provide the foundation for therapeutic strategies aimed at reactivating the paternal UBE3A allele in AS patients.