Hannah Nourie Submitted:

Angelman syndrome results from the loss of the maternal UBE3A allele. In mature neurons, the paternal allele is normally silenced by the long non-coding antisense transcript UBE3A-ATS. This genetic regulation provides a a compelling therapeutic opportunity: reactivation of the intact paternal allele to restore UBE3A expression in neurons.

Our lab has previously identified small molecules capable of unsilencing paternal UBE3A through phenotypic screening, but these compounds were originally developed as chemotherapeutics, limiting their suitability for Angelman syndrome. This underscores the need for unbiased target-driven strategies to uncover safe, druggable regulators of paternal UBE3A silencing.

Progress in defining the neuronal mechanisms of UBE3A-ATS expression has been hindered by challenges of large-scale primary neuron culture and the absence of sensitive, selectable reporters of allele-specific expression. To overcome these barriers, we have established robust protocols for neuron culture and generated a dual-reporter Ube3a-IRES-NanoLuciferase-T2A-Sun1-sfGFP (INSG) mouse model. NanoLuciferase enables rapid, quantitative small-molecule screening, while the Sun1-GFP nuclear reporter supports fluorescence-based sorting for genetic screens.