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 imprin ting are just beginning to be understood. However, the tendency of imprinte d genes to exist in chromosomal clusters suggests a sharing of regulatory e lements. To better understand imprinted gene clustering, we disrupted a clu ster of imprinted genes on mouse distal chromosome 7 using the Cre/loxP rec ombination system. In mice carrying a site-specific translocation separatin g Cdkn1c and Kcnq1, imprinting of the genes retained on chromosome 7, inclu ding Kcnq1, Kcnq1ot1, Ascl2, H19 and lgf2, is unaffected, demonstrating tha t these genes are not regulated by elements near or telomeric to Cdkn1c. In contrast, expression and imprinting of the translocated Cdkn1c, Slc22a1l a nd Tssc3 on chromosome 11 are affected, consistent with the hypothesis that elements regulating both expression and imprinting of these genes lie with in or proximal to Kcnq1. These data support the proposal that chromosomal a bnormalities, including translocations, within KCNQ1 that are associated wi th the human disease Beckwith-Wiedemann syndrome (BWS) may disrupt CDKN1C e xpression. These results underscore the importance of gene clustering for t he proper regulation of imprinted genes.