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Molecular and Cellular Biology, August 2003, p. 5475-5488, Vol. 23, No. 16
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.16.5475-5488.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Epigenetic Properties and Identification of an Imprint Mark in the Nesp-Gnasxl Domain of the Mouse Gnas Imprinted Locus

Candice Coombes,1,{dagger} Philippe Arnaud,1 Emma Gordon,1 Wendy Dean,1 Elizabeth A. Coar,1 Christine M. Williamson,2 Robert Feil,3 Jo Peters,2 and Gavin Kelsey1*

Developmental Genetics Programme, The Babraham Institute, Cambridge CB2 4AT,1 MRC Mammalian Genetics Unit, Harwell, Didcot, Oxfordshire OX11 0RD, United Kingdom,2 Institute of Molecular Genetics, CNRS, UMR-5535, 34293 Montpellier, France3

Received 20 December 2002/ Returned for modification 7 April 2003/ Accepted 20 May 2003

The Gnas locus in the mouse is imprinted with a complex arrangement of alternative transcripts defined by promoters with different patterns of monoallelic expression. The Gnas transcript is subject to tissue-specific imprinted expression, Nesp is expressed only from the maternal allele, and Gnasxl is expressed only from the paternal allele. The mechanisms controlling these expression patterns are not known. To identify potential imprinting regulatory regions, particularly for the reciprocally expressed Nesp and Gnasxl promoters, we examined epigenetic properties of the locus in gametes, embryonic stem cells, and fetal and adult tissues. The Nesp and Gnasxl promoter regions are contained in extensive CpG islands with methylation of the paternal allele at Nesp and the maternal allele at Gnasxl. Parental allele-specific DNase I-hypersensitive sites were found at these regions, which correlate with hypomethylation rather than actual expression status. A germ line methylation mark was identified covering the promoters for Gnasxl and the antisense transcript Nespas. Prominent DNase I-hypersensitive sites present on paternal alleles in embryonic stem cells are contained within this mark. This is the second gametic mark identified at Gnas and suggests that the Nesp and Gnasxl promoters are under separate control from the Gnas promoter. We propose models to account for the regulation of imprinting at the locus.

* Corresponding author. Mailing address: Developmental Genetics Programme, The Babraham Institute, Cambridge CB2 4AT, United Kingdom. Phone: 44-1223 496332. Fax: 44-1223 496022. E-mail: gavin.kelsey{at}bbsrc.ac.uk.

{dagger} Present address: Johns Hopkins University, Baltimore, MD 21231.

Molecular and Cellular Biology, August 2003, p. 5475-5488, Vol. 23, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.16.5475-5488.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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