MULTIPLE MECHANISMS REGULATE IMPRINTING OF THE MOUSE DISTAL CHROMOSOME-7 GENE-CLUSTER

Genomic imprinting is an epigenetic process that results in the prefer ential silencing of one of the two parental copies of a gene. Although the precise mechanisms by which genomic imprinting occurs are unknown , the tendency of imprinted genes to exist in chromosomal clusters sug gests long-range regulation through shared regulatory elements. We cha racterize a 800-kb region on the distal end of mouse chromosome 7 that contains a cluster of four maternally expressed genes, H19, Mash2, Kv lqt1, and p57(Kip2), as well as two paternally expressed genes, Igf2 a nd Ins2, and assess the expression and imprinting of Mash2, Kvlqt1, an d p57(Kip2) during development in embryonic and extraembryonic tissues . Unlike Igf2 and Ins2, which depend on H19 for their imprinting, Mash 2, p57(Kip2), and Kvlqt1 are unaffected by a deletion of the H19 gene region, suggesting that these more telomeric genes are not regulated b y the mechanism that controls H19, Igf2, and Ins2. Mutations in human p57(Kip2) have been implicated in Beckwith-Wiedemann syndrome, a disea se that has also been associated with loss of imprinting of IGF2. We f ind, however, that a deletion of the gene has no effect on imprinting within the cluster. Surprisingly, the three maternally expressed genes are regulated very differently by DNA methylation; p57(Kip2) activate d, Kvlqt1 is silenced, and Mash2 is unaffected in mice lacking DNA met hyltransferase. We conclude that H19 is not a global regulator of impr inting on distal chromosome 7 and that the telomeric genes are imprint ed by a separate mechanism(s).