A bipartite boundary element restricts imprinting to mature neurons.

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function from the maternal allele of , a gene encoding an E3 ubiquitin ligase. is only expressed from the maternally inherited allele in mature human neurons due to tissue-specific genomic imprinting. Imprinted expression of is restricted to neurons by expression of () from the paternally inherited allele, which silences the paternal allele of in However, the mechanism restricting expression and imprinting to neurons is not understood. We used CRISPR/Cas9-mediated genome editing to functionally define a bipartite boundary element critical for neuron-specific expression of in humans. Removal of this element led to up-regulation of without repressing paternal However, increasing expression of in the absence of the boundary element resulted in full repression of paternal , demonstrating that imprinting requires both the loss of function from the boundary element as well as the up-regulation of These results suggest that manipulation of the competition between and may provide a potential therapeutic approach for AS.