Establishing the epigenetic status of the Prader-Willi/Angelman imprinting center in the gametes and embryo

Boris Kantor, Yotam Kaufman, Kirill Makedonski, Aharon Razin*, Ruth Shemer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

The Prader-Willi/Angelman imprinted domain on human chromosome 15q11-q13 is regulated by an imprinting control center (IC) composed of a sequence around the SNRPN promoter (PWS-SRO) and a sequence located 35 kb upstream (AS-SRO). We have previously hypothesized that the primary imprint is established on AS-SRO, which then confers imprinting on PWS-SRO. Here we examine this hypothesis using a transgene that includes both AS-SRO and PWS-SRO sequences and carries out the entire imprinting process. The epigenetic features of this transgene resemble those previously observed on the endogenous locus, thus allowing analyses in the gametes and early embryo. We demonstrate that the primary imprint is in fact established in the gametes, creating a differentially methylated CpG cluster (DMR) on AS-SRO, presumably by an adjacent de novo signal (DNS). The DMR and DNS bind specific proteins: an allele-discrimination protein (ADP) and a de novo methylation protein, respectively. ADP, being a maternal protein, is involved in both the establishment of DMR in the gametes and in its maintenance through implantation when methylation of PWS-SRO on the maternal allele takes place. Importantly, while the AS-SRO is required in the gametes to confer methylation on PWS-SRO, it is dispensable later in development.

Original languageAmerican English
Pages (from-to)2767-2779
Number of pages13
JournalHuman Molecular Genetics
Volume13
Issue number22
DOIs
StatePublished - 15 Nov 2004

Bibliographical note

Funding Information:
We are grateful to Dr Ben-Zion Tsuberi for help in generating the numerous transgenic lines and thank Liron Abuhatzira for here help in screening the transgenic mice. Special thanks to Dr Agnes Yeivin for helping us in dissecting E 7.5 embryos. Parthenogenetic and androgenetic ES cells were obtained from Drs Wolf Reik and Wendy Dean. This work was supported by the Israel Science Foundation, and grants from the N.I.H. and March of Dimes to A.R. B.K. is a recipient of the Golda Meir Fellowship for an outstanding graduate student.

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