The IC-SNURF-SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A

Abstract

The imprinted domain on human chromosome 15 consists of two oppositely imprinted gene clusters, which are under the coordinated control of an imprinting center (IC) at the 5' end of the SNURF-SNRPN gene. One gene cluster spans the centromeric part of this domain and contains several genes that are transcribed from the paternal chromosome only (MKRN3, MAGEL2, NDN, SNURF-SNRPN, HBII-13, HBII-85 and HBII-52). Apart from the HBII small nucleolar RNA (snoRNA) genes, each of these genes is associated with a 5' differentially methylated region (DMR). The second gene cluster maps to the telomeric part of the imprinted domain and contains two genes (UBE3A and ATP10C), which in some tissues are preferentially expressed from the maternal chromosome. So far, no DMR has been identified at these loci. Instead, maternal-only expression of UBE3A may be regulated indirectly through a paternally expressed antisense transcript. We report here that a processed antisense transcript of UBE3A starts at the IC. The SNURF-SNRPN sense/UBE3A antisense transcription unit spans more than 460 kb and contains at least 148 exons, including the previously identified IPW exons. It serves as the host for the previously identified HBII-13, HBII-85 and HBII-52 snoRNAs as well as for four additional snoRNAs (HBII-436, HBII-437, HBII-438A and HBII-438B), newly identified in this study. Almost all of those snoRNAs are encoded within introns of this large transcript. Northern blot analysis indicates that most if not all of these snoRNAs are indeed expressed by processing from these introns. As we have not obtained any evidence for other genes in this region, which, from the mouse data appears to be critical for the neonatal Prader-Willi syndrome phenotype, a lack of these snoRNAs may be causally involved in this disease.

Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer

“…A role for noncoding RNAs is implicated in the regulation of imprinted genes due to the preponderance of these transcribed sequences located in imprinted domains and empirical data suggesting their importance (26,27,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). For example, the genes Delta, Drosophila homologue-like 1 (DLK1) and maternally expressed gene 3 (MEG3) in the imprinted domain on human chromosome 14 bear remarkable similarity to the IGF2/H19 domain in terms of the genomic organization and putative regulatory features (43)(44)(45).…”

Prader-Willi syndrome

“…The UBE3A antisense transcript also arises from transcription of SNURF-SNRPN and is thought to lead to the repression of the paternally inherited UBE3A gene in humans and mice. [98][99][100] The snoRNAs are present in single copy except for SNORD116 (previously named HBII-85) and SNORD115 (previously named HBII-52), which are present in 29 and 42 copies, respectively. It is thought that the snoRNAs are probably involved in the modification of mRNA by alternative splicing and that each snoRNA gene might have multiple targets.…”

Clinical and genetic aspects of Angelman syndrome

“…44 Because no differentially methylated promoter region is present in UBE3A, it has been proposed that the imprinted expression of UBE3A may be regulated indirectly through a paternally expressed antisense transcript. 93 Runte et al 94 have shown that a long SNURF-SNRPN sense/ UBE3A antisense RNA transcript exists in the AS/PWS region, starting from the SNURF-SNRPN imprinting center (IC) and extending more than 460 kb to at least the 5Ј end of UBE3A. It has been proposed that this UBE3A antisense transcript blocks paternal UBE3A gene expression.…”