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Asymmetric regulation of imprinting on the maternal and paternal chromosomes at the Dlk1-Gtl2 imprinted cluster on mouse chromosome 12

Nature Genetics volume 35, pages 97–102 (2003)Cite this article

Abstract

Genomic imprinting causes parental origin–specific gene expression1. Cis-acting regulatory elements that control imprinting are not fully understood but involve regions that become differentially methylated on the two parental chromosomes during male and female gametogenesis2,3,4. Understanding properties of maternally and paternally inherited imprints provides insight into the mechanisms and evolution of genomic imprinting. Previously we identified an intergenic germline-derived differentially methylated region (IG-DMR) that is a candidate control element for an imprinted domain on distal mouse chromosome 12 (ref. 5). The 1-Mb cluster contains the paternally expressed protein-coding genes Dlk1 (refs. 6,7) and Dio3 (ref. 8,9) and several maternally expressed non-coding RNAs, including Gtl2 (refs. 6,7,10) and C/D snoRNAs11. A retrotransposon-like gene (Rtl1) is expressed from the paternal chromosome and has an antisense transcript expressed from the maternal chromosome containing two microRNAs with full complementarity to Rtl1 (ref. 12). Here we show that deletion of the IG-DMR from the maternally inherited chromosome causes bidirectional loss of imprinting of all genes in the cluster. When the deletion is transmitted from the father, imprinting is unaltered. These results prove that the IG-DMR is a control element for all imprinted genes on the maternal chromosome only and indicate that the two parental chromosomes control allele-specific gene expression differently.

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Figure 1: Targeted deletion of the IG-DMR upstream of Gtl2 on mouse chromosome 12.
Figure 2: Expression of imprinted genes as a consequence of the IG-DMR deletion.
Figure 3: Biallelic expression of Dlk1, Rtl1 and Dio3 after maternal transmission of IG-DMR deletion.
Figure 4: Promoter methylation at Gtl2 is altered in the absence of the IG-DMR.
Figure 5: Differential methylation at the IG-DMR is conserved in mouse and human.
Figure 6: Summary of imprinted gene expression after maternal and paternal transmission of the IG-DMR deletion.

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Acknowledgements

We thank D. Barlow, G. Kelsey and members of the laboratory of A.C.F.-S. for discussions of this work; P.-W. Teng and A. Woodhouse for technical assistance; M. George and E. Saunders of the Babraham Gene Targeting Facility for ES cell culture and blastocyst injection; R. Voutilainen for assistance with the cell cultures; and M. Constancia for advice with the targeting construct. This work was supported by grants from the UK Medical Research Council and Cancer Research UK. S.-P.L. is funded by a graduate research scholarship from the Taiwanese Government, N.Y. by a BBSRC studentship and H.S. by a PhD fellowship from the Allocation de Moniteur Normalien.

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Author notes

  1. Shuji Takada

    Present address: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, 4072, Australia

  2. Martina Paulsen

    Present address: Universität des Saarlandes, FR Genetik, Postfach 151150, D-66041, Saarbrücken, Germany

Authors and Affiliations

  1. Department of Anatomy, University of Cambridge, Downing Street, Cambridge, CB2 3DY, UK

    Shau-Ping Lin, Neil Youngson, Shuji Takada, Martina Paulsen & Anne C Ferguson-Smith

  2. LBME-CNRS (UMR5099), Université P. Sabatier, 118 Route de Narbonne, Toulouse, 31062, Cedex, France

    Hervé Seitz & Jerome Cavaille

  3. Laboratory of Developmental Genetics and Imprinting, Developmental Genetics Programme, The Babraham Institute, Cambridge, CB2 4AT, UK

    Wolf Reik

  4. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, 4072, Australia

    Martina Paulsen

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Lin, SP., Youngson, N., Takada, S. et al. Asymmetric regulation of imprinting on the maternal and paternal chromosomes at the Dlk1-Gtl2 imprinted cluster on mouse chromosome 12. Nat Genet 35, 97–102 (2003). https://doi.org/10.1038/ng1233

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