Abstract
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
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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).
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).
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).
Maher, E.R. & Reik, W.P. Beckwith-Wiedemann syndrome: imprinting in clusters revisited. J. Clin. Invest. 105, 247–252 (2000).
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).
Hatada, I. et al. An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome. Nature Genet. 14, 171–173 (1996).
Lee, M.P. et al. Low frequency of p57KIP2 mutation in Beckwith-Wiedemann syndrome. Am. J. Hum. Genet. 61, 304–309 (1997).
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).
Ramirez-Solis, R., Liu, P. & Bradley, A. Chromosome engineering in mice. Nature 378, 720–724 (1995).
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).
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).
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).
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).
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).
Dao, D. et al. IMPT1, an imprinted gene similar to polyspecific transporter and multi-drug resistance genes. Hum. Mol. Genet. 7, 597–608 (1998).
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).
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).
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).
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).
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).
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).
Thorvaldsen, J.L. & Bartolomei, M.S. Molecular biology. Mothers setting boundaries. Science 288, 2145–2146 (2000).
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).
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).
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).
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).
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).
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).
Robertson, E.J. Teratocarcinomas and Embryonic Stem Cells: A Practical Approach 108–110 (IRL Press, Oxford, UK, 1987).
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).
Acknowledgements
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
Rights 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). https://doi.org/10.1038/ng715
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng715
This article is cited by
-
Imprinting on distal chromosome 7 in the placenta involves repressive histone methylation independent of DNA methylation
Nature Genetics (2004)
-
Biallelic expression of HRAS and MUCDHL in human and mouse
Human Genetics (2003)
-
The Tnfrh1 (Tnfrsf23) gene is weakly imprinted in several organs and expressed at the trophoblast-decidua interface
BMC Genetics (2002)
-
Loss of methylation at chromosome 11p15.5 is common in human adult tumors
Oncogene (2002)
-
Regional loss of imprinting and growth deficiency in mice with a targeted deletion of KvDMR1
Nature Genetics (2002)