Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by maternal deficiency of the imprinted gene UBE3A . Individuals with AS suffer from intellectual disability, speech impairment, and motor dysfunction. Currently there is no cure for the disease. Here, we evaluated the phenotypic effect of activating the silenced paternal allele of Ube3a by depleting its antisense RNA Ube3a-ATS in mice. Premature termination of Ube3a-ATS by poly(A) cassette insertion activates expression of Ube3a from the paternal chromosome, and ameliorates many disease-related symptoms in the AS mouse model, including motor coordination defects, cognitive deficit, and impaired long-term potentiation. Studies on the imprinting mechanism of Ube3a revealed a pattern of biallelic transcription initiation with suppressed elongation of paternal Ube3a , implicating transcriptional collision between sense and antisense polymerases. These studies demonstrate the feasibility and utility of unsilencing the paternal copy of Ube3a via targeting Ube3a-ATS as a treatment for Angelman syndrome. Author Summary Angelman syndrome (AS) is a devastating neurodevelopmental disorder diagnosed in young children, currently with no effective treatments. It is characterized by absence of speech, ataxia, intellectual disability, epilepsy, and a characteristic behavior of frequent laughter and smiling. The disease is caused by loss of the maternal allele of UBE3A , which is preferentially silenced on the paternal chromosome and expressed on the maternal chromosome in neurons due to genomic imprinting. It has been long proposed that by activating the originally silenced paternal allele of UBE3A , the disease may be cured. Here in our research, we demonstrated the feasibility of activating paternal Ube3a in mice by terminating the transcription of its antisense RNA Ube3a-ATS genetically. In the AS mouse model who additionally receives the terminated Ube3a-ATS allele from the paternal side, we observed restoration of Ube3a expression, amelioration of behavioral defects and reversal of the impaired long-term potentiation. We further studied the imprinting mechanisms of Ube3a and proposed a novel transcriptional collision model. These results provide solid in vivo evidence for a key regulatory role of Ube3a-ATS in the disease and open up an exciting possibility of a gene-specific treatment for Angelman syndrome.
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