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Molecular and Cellular Biology, November 2006, p. 8347-8356, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00981-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Specific Differentially Methylated Domain Sequences Direct the Maintenance of Methylation at Imprinted Genes{triangledown}

Bonnie Reinhart,1 Ariane Paoloni-Giacobino,1 and J. Richard Chaillet1,2,3*

Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213,1 Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania 15213,2 Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania 152133

Received 1 June 2006/ Returned for modification 31 July 2006/ Accepted 28 August 2006

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.

* Corresponding author. Mailing address: Department of Molecular Genetics and Biochemistry, University of Pittsburgh, 200 Lothrop Street, W1257 Biomedical Science Tower, Pittsburgh, PA 15213. Phone: (412) 383-7974. Fax: (412) 383-7984. E-mail: chaillet{at}pitt.edu.

{triangledown} Published ahead of print on 5 September 2006.

Molecular and Cellular Biology, November 2006, p. 8347-8356, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00981-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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