Regulation of the large (approximately 1000 kb) imprinted murine Ube3a antisense transcript by alternative exons upstream of Snurf/ Snrpn.
Most cases of Angelman syndrome (AS) result from loss or inactivation of ubiquitin protein ligase 3A (UBE3A), a gene displaying maternal-specific expression in brain. Epigenetic silencing of the paternal UBE3A allele in brain appears to be mediated by a non-coding UBE3A antisense (UBE3A- ATS). In human, UBE3A- ATS extends approximately 450 kb to UBE3A from the small nuclear ribonucleoprotein N (SNURF/ SNRPN) promoter region that contains a cis-acting imprinting center (IC). The concept of a single large antisense transcript is difficult to reconcile with the observation that SNURF/ SNRPN shows a ubiquitous pattern of expression while the more distal part of UBE3A- ATS, which overlaps UBE3A, is brain specific. To address this problem, we examined murine transcripts initiating from several alternative exons dispersed within a 500 kb region upstream of Snurf/ Snrpn. Similar to Ube3a- ATS, these upstream (U) exon-containing transcripts are expressed at neuronal stages of differentiation in a cell culture model of neurogenesis. These findings suggest the novel hypothesis that brain-specific transcription of Ube3a- ATS is regulated by the U exons rather than Snurf/ Snrpn exon 1 as previously suggested from human studies. In support of this hypothesis, we describe U-Ube3a- ATS transcripts where U exons are spliced to Ube3a- ATS with the exclusion of Snurf-Snrpn. We also show that the murine U exons have arisen by genomic duplication of segments that include elements of the IC, suggesting that the brain specific silencing of Ube3a is due to multiple alternatively spliced IC-Ube3a- ATS transcripts.[1]References
- Regulation of the large (approximately 1000 kb) imprinted murine Ube3a antisense transcript by alternative exons upstream of Snurf/Snrpn. Landers, M., Bancescu, D.L., Le Meur, E., Rougeulle, C., Glatt-Deeley, H., Brannan, C., Muscatelli, F., Lalande, M. Nucleic Acids Res. (2004) [Pubmed]
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