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Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes

Abstract

Imprinted genes are clustered in domains, and their allelic repression is mediated by imprinting control regions1,2,3. These imprinting control regions are marked by DNA methylation, which is essential to maintain imprinting in the embryo4. To explore how imprinting is regulated in placenta, we studied the Kcnq1 domain on mouse distal chromosome 7. This large domain is controlled by an intronic imprinting control region5,6 and comprises multiple genes that are imprinted in placenta, without the involvement of promoter DNA methylation7,8,9,10. We found that the paternal repression along the domain involves acquisition of trimethylation at Lys27 and dimethylation at Lys9 of histone H3. Eed-Ezh2 Polycomb complexes are recruited to the paternal chromosome and potentially regulate its repressive histone methylation. Studies on embryonic stem cells and early embryos support our proposal that chromatin repression is established early in development and is maintained in the placenta. In the embryo, however, imprinting is stably maintained only at genes that have promoter DNA methylation. These data underscore the importance of histone methylation in placental imprinting and identify mechanistic similarities with X-chromosome inactivation in extraembryonic tissues, suggesting that the two epigenetic mechanisms are evolutionarily linked.

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Figure 1: Description of imprinting in the placenta at the Kcnq1 domain.
Figure 2: The Kcnq1 domain is marked by paternal methylation at H3-Lys9 and H3-Lys27 in placenta, but not in the embryo.
Figure 3: The Kcnq1 domain is imprinted in ES cells and early embryos.
Figure 4: Polycomb group proteins Ezh2, Suz12 and Eed are associated with the repressed paternal chromosome.
Figure 5: A working model for imprinting along the Kcnq1 domain.

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Acknowledgements

We thank R. Gregory for initiating our work on Ascl2, K. Chebli and the IGM Animal Facility for mouse embryology, N. Brockdorff for providing TS cells, and the members of the imprinting group, E. Schwob and E. Andermarcher for discussions and critical reading of the manuscript. This work was supported by grants from Association pour la Recherche sur le Cancer and Human Frontier Science Program to R.F., by a grant from National Institute of Health to Y.Z. and by fellowships from the Ministry of Science and Technology to D.U. and A.W.

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Correspondence to Robert Feil.

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Supplementary information

Supplementary Fig. 1

Quantitative PCR analysis of H3 methylation and acetylation in 9.5-d.p.c. placentae and embryos. (PDF 21 kb)

Supplementary Fig. 2

Quantitative PCR analysis of H3 methylation and acetylation in ES and TS cells. (PDF 18 kb)

Supplementary Table 1

Oligonucleotides used for RT-PCR. (PDF 12 kb)

Supplementary Table 2

Oligonucleotides used for PCR-SSCP analysis. (PDF 612 kb)

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Umlauf, D., Goto, Y., Cao, R. et al. Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes. Nat Genet 36, 1296–1300 (2004). https://doi.org/10.1038/ng1467

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