Multiple mechanisms regulate imprinting of the mouse distal chromosome 7 gene cluster.
Genomic imprinting is an epigenetic process that results in the preferential 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 suggests long-range regulation through shared regulatory elements. We characterize a 800-kb region on the distal end of mouse chromosome 7 that contains a cluster of four maternally expressed genes, H19, Mash2, Kvlqt1, and p57(Kip2), as well as two paternally expressed genes, Igf2 and Ins2, and assess the expression and imprinting of Mash2, Kvlqt1, and p57(Kip2) during development in embryonic and extraembryonic tissues. Unlike Igf2 and Ins2, which depend on H19 for their imprinting, Mash2, p57(Kip2), and Kvlqt1 are unaffected by a deletion of the H19 gene region, suggesting that these more telomeric genes are not regulated by the mechanism that controls H19, Igf2, and Ins2. Mutations in human p57(Kip2) have been implicated in Beckwith-Wiedemann syndrome, a disease that has also been associated with loss of imprinting of IGF2. We find, 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) is activated, Kvlqt1 is silenced, and Mash2 is unaffected in mice lacking DNA methyltransferase. We conclude that H19 is not a global regulator of imprinting on distal chromosome 7 and that the telomeric genes are imprinted by a separate mechanism(s).
Caspary
T
T
Howard Hughes Medical Institute, Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
Cleary
M A
MA
Baker
C C
CC
Guan
X J
XJ
Tilghman
S M
SM
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002874:Chromosome Mapping; D002875:Chromosomes; D050761:Cyclin-Dependent Kinase Inhibitor p57; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D008040:Genetic Linkage; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000235:genetics; D015221:Potassium Channels / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated; D011384:Proinsulin / Q000235:genetics; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D014157:Transcription Factors
D051792:Basic Helix-Loop-Helix Proteins; D050761:Cyclin-Dependent Kinase Inhibitor p57; D015254:DNA Modification Methylases; D004268:DNA-Binding Proteins; D007335:Insulin-Like Growth Factor II; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D009124:Muscle Proteins; D009687:Nuclear Proteins; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011384:Proinsulin; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D014157:Transcription Factors; C065501:ASCL2 protein, human; C489311:Ascl2 protein, mouse; C493964:CDKN1C protein, human; C493965:Cdkn1c protein, mouse; C094335:H19 long non-coding RNA; C496909:KCNQ1 protein, human; C496910:Kcnq1 protein, mouse