title: Regulation of the large (approximately 1000 kb) imprinted murine Ube3a antisense transcript by alternative exons upstream of Snurf/Snrpn.
abstract: 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.
authors.affiliation: Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Landers
authors.forename: Daria L
authors.initials: DL
authors.lastname: Bancescu
authors.forename: Elodie
authors.initials: E
authors.lastname: Le Meur
authors.forename: Claire
authors.initials: C
authors.lastname: Rougeulle
authors.forename: Heather
authors.initials: H
authors.lastname: Glatt-Deeley
authors.forename: Camilynn
authors.initials: C
authors.lastname: Brannan
authors.forename: Françoise
authors.initials: F
authors.lastname: Muscatelli
authors.forename: Marc
authors.initials: M
authors.lastname: Lalande
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D001324:Autoantigens; D001483:Base Sequence; D001921:Brain / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005091:Exons; D020868:Gene Silencing; D018392:Genomic Imprinting; D007438:Introns; D051379:Mice / Q000235:genetics*; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D016372:RNA, Antisense / Q000235:genetics* / Q000378:metabolism; D020537:RNA, Small Nucleolar / Q000378:metabolism; D051381:Rats; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics; D016415:Sequence Alignment; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D055517:snRNP Core Proteins
chemical_list: D001324:Autoantigens; D009687:Nuclear Proteins; D016372:RNA, Antisense; D020537:RNA, Small Nucleolar; D017411:Ribonucleoproteins, Small Nuclear; C526417:SNRPN protein, human; C486713:SNURF protein, mouse; D055517:snRNP Core Proteins; D044767:Ubiquitin-Protein Ligases