A cis-acting control region is required exclusively for the tissue-specific imprinting of Gnas

Christine M Williamson, Simon T Ball, Wade T Nottingham, Judith A Skinner, Antonius Plagge, Martin D Turner, Nicola Powles, Tertius Hough, David Papworth, WD Fraser, Mark Maconochie, Jo Peters

Research output: Contribution to journalArticle

145 Citations (Scopus)


Genomic imprinting brings about allele-specific silencing according to parental origin1. Silencing is controlled by cis-acting regulatory regions that are differentially marked during gametogenesis and can act over hundreds of kilobases to silence many genes2,3,4,5,6. Two candidate imprinting control regions (ICRs) have been identified at the compact imprinted Gnas cluster on distal mouse chromosome 2, one at exon 1A upstream of Gnas itself7 and one covering the promoters for Gnasxl and the antisense Nespas (ref. 8). This imprinted cluster is complex, containing biallelic, maternally and paternally expressed transcripts that share exons9. Gnas itself is mainly biallelically expressed but is weakly paternally repressed in specific tissues10. Here we show that a paternally derived targeted deletion of the germline differentially methylated region at exon 1A abolishes tissue-specific imprinting of Gnas. This rescues the abnormal phenotype of mice with a maternally derived Gnas mutation11,12. Imprinting of alternative transcripts, Nesp, Gnasxl and Nespas (ref. 13), in the cluster is unaffected. The results establish that the differentially methylated region at exon 1A contains an imprinting control element that specifically regulates Gnas and comprises a characterized ICR for a gene that is only weakly imprinted in a minority of tissues. There must be a second ICR regulating the alternative transcripts.
Original languageEnglish
Pages (from-to)894-899
Number of pages6
JournalNature Genetics
Issue number8
Publication statusPublished - Aug 2004

Cite this