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Identification of an imprinting control region affecting the expression of all transcripts in the Gnas cluster


Genomic imprinting results in allele-specific silencing according to parental origin1. Silencing is brought about by imprinting control regions (ICRs) that are differentially marked in gametogenesis2. 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 gene3. 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.

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Figure 1: Gene targeting of the Nespas DMR region and its effect on transcription and methylation of Nesp.
Figure 2: Gnasxl expression is reduced and Gnasxl promoter methylation is unaltered in mice carrying ΔNAS-DMR (KO).
Figure 3: Expression of Exon 1A and the Gnas gene after paternal and maternal transmission of ΔNAS-DMR (KO).
Figure 4: The Exon 1A DMR is partially methylated on the paternal allele when ΔNAS-DMR is paternally inherited.
Figure 5: Summary of the transcriptional and methylation status of the Gnas cluster.

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We thank B.M. Cattanach for comments on the manuscript; D. Papworth for statistical analyses; E.P. Evans for karyotype analysis; J. Bowler for injection of blastocysts; the Harwell Transgenic Facility for technical support for the targeting; the GEMS core at MRC Harwell for sequencing and pyrosequencing; J. Harrison, M. Harrison, L. Jones and A. Cameron for animal husbandry; and A. Ford's group for imaging services. This work was supported by the UK Medical Research Council and by the UK Biotechnology and Biological Sciences Research Council.

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Correspondence to Jo Peters.

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Supplementary information

Supplementary Fig. 1

Sense and antisense promoter activity detected in the Nespas-Gnasxl region of the mouse Gnas imprinting cluster in a cell transfection assay. (PDF 269 kb)

Supplementary Fig. 2

Maternal inheritance of ΔNAS-DMR does not alter the imprinted expression of Nespas, Nesp, Gnasxl or Exon 1A. (PDF 439 kb)

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Williamson, C., Turner, M., Ball, S. et al. Identification of an imprinting control region affecting the expression of all transcripts in the Gnas cluster. Nat Genet 38, 350–355 (2006).

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