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

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.

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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.

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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.

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Correspondence to Shirley M. Tilghman.

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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

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