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The Angelman syndrome gene,  UBE3A , is subject to genomic imprinting controlled by mechanisms that are only partially understood. Its antisense transcript,  UBE3A-ATS , is also imprinted and hypothesized to suppress  UBE3A in cis . In this research, we showed that the mouse antisense ortholog,  Ube3a-ATS , was transcribed by RNA polymerase (RNAP) II. However, unlike typical protein-coding transcripts,  Ube3a-ATS  was not poly-adenylated and was localized exclusively in the nucleus. It was relatively unstable with a half-life of 4 h, shorter than most protein-coding RNAs tested. To understand the role of  Ube3a-ATS in vivo , a mouse model with a 0.9-kb genomic deletion over the paternal  Snrpn  major promoter was studied. The mice showed partial activation of paternal  Ube3a , with decreased expression of  Ube3a-ATS  but not any imprinting defects in the Prader–Willi syndrome/Angelman syndrome region. A novel cell culture model was also generated with a transcriptional termination cassette inserted downstream of  Ube3a  on the paternal chromosome to reduce  Ube3a-ATS  transcription. In neuronally differentiated embryonic stem (ES) cells, paternal  Ube3a  was found to be expressed at a high level, comparable with that of the maternal allele. To further characterize the antisense RNA, a strand-specific microarray was performed.  Ube3a-ATS  was detectable across the entire locus of  Ube3a  and extended beyond the transcriptional start site of  Ube3a . In summary, we conclude that  Ube3a-ATS  is an atypical RNAPII transcript that represses  Ube3a  on the paternal chromosome. These results suggest that the repression of human  UBE3A-ATS  may activate the expression of  UBE3A  from the paternal chromosome, providing a potential therapeutic strategy for patients with Angelman syndrome.

Ube3a-ATS is an atypical RNA polymerase II transcript that represses the paternal expression of Ube3a