title: Identification of an imprinting control region affecting the expression of all transcripts in the Gnas cluster.
abstract: Genomic imprinting results in allele-specific silencing according to parental origin. Silencing is brought about by imprinting control regions (ICRs) that are differentially marked in gametogenesis. The group of imprinted transcripts in the mouse Gnas cluster (Nesp, Nespas, Gnasxl, Exon 1A and Gnas) provides a model for analyzing the mechanisms of imprint regulation. We previously identified an ICR that specifically regulates the tissue-specific imprinted expression of the Gnas gene. Here we identify a second ICR at the Gnas cluster. We show that a paternally derived targeted deletion of the germline differentially methylated region (DMR) associated with the antisense Nespas transcript unexpectedly affects both the expression of all transcripts in the cluster and methylation of two DMRs. Our results establish that the Nespas DMR is the principal ICR at the Gnas cluster and functions bidirectionally as a switch for modulating expression of the antagonistically acting genes Gnasxl and Gnas. Uniquely, the Nespas DMR acts on the downstream ICR at exon 1A to regulate tissue-specific imprinting of the Gnas gene.
authors.affiliation: MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Williamson
authors.forename: Martin D
authors.initials: MD
authors.lastname: Turner
authors.forename: Simon T
authors.initials: ST
authors.lastname: Ball
authors.forename: Wade T
authors.initials: WT
authors.lastname: Nottingham
authors.forename: Peter
authors.initials: P
authors.lastname: Glenister
authors.forename: Martin
authors.initials: M
authors.lastname: Fray
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Tymowska-Lalanne
authors.forename: Antonius
authors.initials: A
authors.lastname: Plagge
authors.forename: Nicola
authors.initials: N
authors.lastname: Powles-Glover
authors.forename: Gavin
authors.initials: G
authors.lastname: Kelsey
authors.forename: Mark
authors.initials: M
authors.lastname: Maconochie
authors.forename: Jo
authors.initials: J
authors.lastname: Peters
mesh_terms: D000818:Animals; D002864:Chromogranins; D019175:DNA Methylation; D005091:Exons; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D018392:Genomic Imprinting; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D016372:RNA, Antisense / Q000235:genetics*; D022661:RNA, Untranslated / Q000235:genetics*; D017384:Sequence Deletion; D014158:Transcription, Genetic
chemical_list: D002864:Chromogranins; D016372:RNA, Antisense; D022661:RNA, Untranslated; C498642:Gnas protein, mouse; D019205:GTP-Binding Protein alpha Subunits, Gs