Specific differentially methylated domain sequences direct the maintenance of methylation at imprinted genes.
Landmark features of imprinted genes are differentially methylated domains (DMDs), in which one parental allele is methylated on CpG dinucleotides and the opposite allele is unmethylated. Genetic experiments in the mouse have shown that DMDs are required for the parent-specific expression of linked clusters of imprinted genes. To understand the mechanism whereby the differential methylation is established and maintained, we analyzed a series of transgenes containing DMD sequences and showed that imperfect tandem repeats from DMDs associated with the Snurf/Snrpn, Kcnq1, and Igf2r gene clusters govern transgene imprinting. For the Igf2r DMD the minimal imprinting signal is two unit copies of the tandem repeat. This imprinted transgene behaves identically to endogenous imprinted genes in Dnmt1o and Dnmt3L mutant mouse backgrounds. The primary function of the imprinting signal within the transgene DMD is to maintain, during embryogenesis and a critical period of genomic reprogramming, parent-specific DNA methylation states established in the germ line. This work advances our understanding of the imprinting mechanism by defining a genomic signal that dependably perpetuates an epigenetic state during postzygotic development.
Reinhart
Bonnie
B
Department of Molecular Genetics and Biochemistry, University of Pittsburgh, W1257 Biomedical Science Tower, Pittsburgh, PA 15213, USA.
Paoloni-Giacobino
Ariane
A
Chaillet
J Richard
JR
D000818:Animals; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D005786:Gene Expression Regulation; D005803:Genes, Immunoglobulin; D016259:Genes, myc; D018392:Genomic Imprinting; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000235:genetics*; D017527:Receptor, IGF Type 2 / Q000235:genetics*; D020080:Tandem Repeat Sequences
D009687:Nuclear Proteins; D017527:Receptor, IGF Type 2; C486713:SNURF protein, mouse; C498796:Dnmt3l protein, mouse; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse