Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Disruption of an imprinted gene cluster by a targeted chromosomal translocation in mice


Genomic imprinting is an epigenetic process in which the activity of a gene is determined by its parent of origin. Mechanisms governing genomic imprinting are just beginning to be understood. However, the tendency of imprinted genes to exist in chromosomal clusters suggests a sharing of regulatory elements. To better understand imprinted gene clustering, we disrupted a cluster of imprinted genes on mouse distal chromosome 7 using the Cre/loxP recombination system. In mice carrying a site-specific translocation separating Cdkn1c and Kcnq1, imprinting of the genes retained on chromosome 7, including Kcnq1, Kcnq1ot1, Ascl2, H19 and Igf2, is unaffected, demonstrating that these genes are not regulated by elements near or telomeric to Cdkn1c. In contrast, expression and imprinting of the translocated Cdkn1c, Slc22a1l and Tssc3 on chromosome 11 are affected, consistent with the hypothesis that elements regulating both expression and imprinting of these genes lie within or proximal to Kcnq1. These data support the proposal that chromosomal abnormalities, including translocations, within KCNQ1 that are associated with the human disease Beckwith-Wiedemann syndrome (BWS) may disrupt CDKN1C expression. These results underscore the importance of gene clustering for the proper regulation of imprinted genes.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Site of imprinted gene cluster disruption, targeting approach and Cre recombination strategy.
Figure 2: DNA FISH analysis of ES cells carrying the translocation.
Figure 3: Genes retained on chromosome 7 are unaffected by the translocation.
Figure 4: Gene expression and imprinting are deregulated by translocation of distal chromosome 7 genes to chromosome 11.


  1. Leighton, P.A., Ingram, R.S., Eggenschwiler, J., Efstratiadis, A. & Tilghman, S.M. Disruption of imprinting caused by deletion of the H19 gene region in mice. Nature 375, 34–39 (1995).

    Article  CAS  Google Scholar 

  2. Thorvaldson, J.L., Duran, K.L. & Bartolomei, M.S. Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2. Genes Dev. 12, 3693–3702 (1998).

    Article  Google Scholar 

  3. Caspary, T., Cleary, M.A., Baker, C.C., Guan, X.-J. & Tilghman, S.M. Multiple mechanisms regulate imprinting of the mouse distal chromosome 7 gene cluster. Mol. Cell. Biol. 18, 3466–3474 (1998).

    Article  CAS  Google Scholar 

  4. Maher, E.R. & Reik, W.P. Beckwith-Wiedemann syndrome: imprinting in clusters revisited. J. Clin. Invest. 105, 247–252 (2000).

    Article  CAS  Google Scholar 

  5. Brown, K.W. et al. Imprinting mutation in the Beckwith-Wiedemann syndrome leads to biallelic IGF2 expression through an H19-independent pathway. Hum. Mol. Genet. 5, 2027–2032 (1996).

    Article  CAS  Google Scholar 

  6. Hatada, I. et al. An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome. Nature Genet. 14, 171–173 (1996).

    Article  CAS  Google Scholar 

  7. Lee, M.P. et al. Low frequency of p57KIP2 mutation in Beckwith-Wiedemann syndrome. Am. J. Hum. Genet. 61, 304–309 (1997).

    Article  CAS  Google Scholar 

  8. O'Keefe, D. et al. Coding mutations in p57KIP2 are present in some cases of Beckwith-Wiedemann syndrome but are rare or absent in Wilms tumors. Am. J. Hum. Genet. 61, 295–303 (1997).

    Article  CAS  Google Scholar 

  9. Ramirez-Solis, R., Liu, P. & Bradley, A. Chromosome engineering in mice. Nature 378, 720–724 (1995).

    Article  CAS  Google Scholar 

  10. Smith, A.J. et al. A site-directed chromosomal translocation induced in embryonic stem cells by Cre-loxP recombination. Nature Genet. 9, 376–385 (1995).

    Article  CAS  Google Scholar 

  11. Van Deursen, J., Fornerod, M., Van Rees, B. & Grosveld, G. Cre-mediated site-specific translocation between nonhomologous mouse chromosomes. Proc. Natl. Acad. Sci. USA 92, 7376–7380 (1995).

    Article  CAS  Google Scholar 

  12. Zheng, B., Sage, M., Sheppeard, E.A., Jurecic, V. & Bradley, A. Engineering mouse chromosomes with Cre-loxP: range, efficiency, and somatic applications. Mol. Cell. Biol. 20, 648–655 (2000).

    Article  CAS  Google Scholar 

  13. Yan, Y., Frisén, J., Lee, M.H., Massagué, J. & Barbacid, M. Ablation of the CDK inhibitor p57KIP2 results in increased apoptosis and delayed differentiation during mouse development. Genes Dev. 11, 973–983 (1997).

    Article  CAS  Google Scholar 

  14. Zhang, P. et al. Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome. Nature 387, 151–158 (1997).

    Article  CAS  Google Scholar 

  15. Dao, D. et al. IMPT1, an imprinted gene similar to polyspecific transporter and multi-drug resistance genes. Hum. Mol. Genet. 7, 597–608 (1998).

    Article  CAS  Google Scholar 

  16. Qian, N. et al. The IPL gene on chromosome 11p15.5 is imprinted in humans and mice and is similar to TDAG51, implicated in Fas expression and apoptosis. Hum. Mol. Genet. 6, 2021–2029 (1997).

    Article  CAS  Google Scholar 

  17. Paulsen, M. et al. Sequence conservation and variability of imprinting in the Beckwith-Wiedemann syndrome gene cluster in human and mouse. Hum. Mol. Genet. 9, 1829–1841 (2000).

    Article  CAS  Google Scholar 

  18. Lee, M.P. et al. Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLQT1, occurs frequently in Beckwith-Wiedemann syndrome and is independent of insulin-like growth factor II imprinting. Proc. Natl. Acad. Sci. USA 96, 5203–5208 (1999).

    Article  CAS  Google Scholar 

  19. Mitsuya, K. et al. LIT1, an imprinted antisense RNA in the human KvLQT1 locus identified by screening for differentially expressed transcripts using monochromosomal hybrids. Hum. Mol. Genet. 8, 1209–1217 (1999).

    Article  CAS  Google Scholar 

  20. Smilinich, N.J. et al. A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith- Wiedemann syndrome. Proc. Natl. Acad. Sci. USA 96, 8064–8069 (1999).

    Article  CAS  Google Scholar 

  21. Horike, S. et al. Targeted disruption of the human LIT1 locus defines a putative imprinting control element playing an essential role in Beckwith-Wiedemann syndrome. Hum. Mol. Genet. 9, 2075–2083 (2000).

    Article  CAS  Google Scholar 

  22. Thorvaldsen, J.L. & Bartolomei, M.S. Molecular biology. Mothers setting boundaries. Science 288, 2145–2146 (2000).

    Article  CAS  Google Scholar 

  23. Cooper, P.R. et al. Divergently transcribed overlapping genes expressed in liver and kidney and located in the 11p15.5 imprinted domain. Genomics 49, 38–51 (1998).

    Article  CAS  Google Scholar 

  24. Onyango, P. et al. Sequence and comparative analysis of the mouse 1-megabase region orthologous to the human 11p15 imprinted domain. Genome Res. 10, 1697–1710 (2000).

    Article  CAS  Google Scholar 

  25. Yatsuki, H. et al. Sequence-based structural features between Kvlqt1 and Tapa1 on mouse chromosome 7F4/F5 corresponding to the Beckwith-Wiedemann syndrome region on human 11p15.5: long-stretches of unusually well conserved intronic sequences of Kvlqt1 between mouse and human. DNA Res. 7, 195–206 (2000).

    Article  CAS  Google Scholar 

  26. Lee, M.P. et al. Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice. J. Clin. Invest. 106, 1447–1455 (2000).

    Article  CAS  Google Scholar 

  27. Casimiro, M.C. et al. Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome. Proc. Natl. Acad. Sci. USA 98, 2526–2531 (2001).

    Article  CAS  Google Scholar 

  28. O'Gorman, S., Dagenais, N.A., Qian., M. & Marchuk, Y. Protamine-Cre recombinase transgenes efficiently recombine target sequences in the male germ line of mice, but not in embryonic stem cells. Proc. Natl. Acad. Sci. USA 94, 14602–14607 (1997).

    Article  CAS  Google Scholar 

  29. Robertson, E.J. Teratocarcinomas and Embryonic Stem Cells: A Practical Approach 108–110 (IRL Press, Oxford, UK, 1987).

  30. Bartolomei, M.S., Webber, A.L., Brunkow, M.E. & Tilghman, S.M. Epigenetic mechanisms underlying the imprinting of the mouse H19 gene. Genes Dev. 7, 1663–1673 (1993).

    Article  CAS  Google Scholar 

Download references


We thank W. Bickmore, M.C. Hollander and A.J. Fornace for advice on preparing metaphase spreads and FISH analysis; R.S. Ingram for sequence data and analysis and help with the design of imprinting assays; T. Caspary for help with maintenance of the mice; G. Guan and B. Jones for assistance with RNA preps; and members of the Tilghman laboratory for helpful comments and suggestions. M.A.C. was a Life Sciences Research Foundation Fellow sponsored by HHMI. This work was supported by a grant from the NIGMS.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Shirley M. Tilghman.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cleary, M., van Raamsdonk, C., Levorse, J. et al. Disruption of an imprinted gene cluster by a targeted chromosomal translocation in mice. Nat Genet 29, 78–82 (2001).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing