title: Transcription is required to establish maternal imprinting at the Prader-Willi syndrome and Angelman syndrome locus.
abstract: The Prader-Willi syndrome (PWS [MIM 17620]) and Angelman syndrome (AS [MIM 105830]) locus is controlled by a bipartite imprinting center (IC) consisting of the PWS-IC and the AS-IC. The most widely accepted model of IC function proposes that the PWS-IC activates gene expression from the paternal allele, while the AS-IC acts to epigenetically inactivate the PWS-IC on the maternal allele, thus silencing the paternally expressed genes. Gene order and imprinting patterns at the PWS/AS locus are well conserved from human to mouse; however, a murine AS-IC has yet to be identified. We investigated a potential regulatory role for transcription from the Snrpn alternative upstream exons in silencing the maternal allele using a murine transgene containing Snrpn and three upstream exons. This transgene displayed appropriate imprinted expression and epigenetic marks, demonstrating the presence of a functional AS-IC. Transcription of the upstream exons from the endogenous locus correlates with imprint establishment in oocytes, and this upstream exon expression pattern was conserved on the transgene. A transgene bearing targeted deletions of each of the three upstream exons exhibited loss of imprinting upon maternal transmission. These results support a model in which transcription from the Snrpn upstream exons directs the maternal imprint at the PWS-IC.
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, United States of America.
authors.forename: Emily Y
authors.initials: EY
authors.lastname: Smith
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Futtner
authors.forename: Stormy J
authors.initials: SJ
authors.lastname: Chamberlain
authors.forename: Karen A
authors.initials: KA
authors.lastname: Johnstone
authors.forename: James L
authors.initials: JL
authors.lastname: Resnick
mesh_terms: D000483:Alleles; D017204:Angelman Syndrome / Q000235:genetics*; D000818:Animals; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics; D005091:Exons; D005786:Gene Expression Regulation; D056426:Genetic Loci; D018392:Genomic Imprinting; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009865:Oocytes / Q000378:metabolism; D011218:Prader-Willi Syndrome / Q000235:genetics*; D023121:RNA, Messenger, Stored / Q000235:genetics; D014158:Transcription, Genetic; D055517:snRNP Core Proteins / Q000235:genetics*
chemical_list: D023121:RNA, Messenger, Stored; D055517:snRNP Core Proteins