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PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos

Abstract

The modification of DNA by 5-methylcytosine (5mC) has essential roles in cell differentiation and development through epigenetic gene regulation1. 5mC can be converted to another modified base, 5-hydroxymethylcytosine (5hmC), by the tet methylcytosine dioxygenase (Tet) family of enzymes2,3. Notably, the balance between 5hmC and 5mC in the genome is linked with cell-differentiation processes such as pluripotency and lineage commitment4,5,6,7. We have previously reported that the maternal factor PGC7 (also known as Dppa3, Stella) is required for the maintenance of DNA methylation in early embryogenesis, and protects 5mC from conversion to 5hmC in the maternal genome8,9. Here we show that PGC7 protects 5mC from Tet3-mediated conversion to 5hmC by binding to maternal chromatin containing dimethylated histone H3 lysine 9 (H3K9me2) in mice. In addition, imprinted loci that are marked with H3K9me2 in mature sperm are protected by PGC7 binding in early embryogenesis. This type of regulatory mechanism could be involved in DNA modifications in somatic cells as well as in early embryos.

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Figure 1: Preferential binding of PGC7 to H3K9me2-marked chromatin.
Figure 2: Protection of the maternal genome from DNA demethylation by PGC7 through H3K9me2-containing chromatin in early embryos.
Figure 3: Remaining H3K9me2 at the DMRs of two paternally imprinted genes, H19 and Rasgrf1 , in mature sperm.
Figure 4: Protection of the conversion of 5mC to 5hmC by PGC7 through H3K9me2-containing chromatin in early embryos.

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Acknowledgements

We thank M. Okano, H. Niwa and H. Kimura for providing Dnmt1−/−Dnmt3a−/−Dnmt3b−/−ES cells, plasmids and antibody. We also thank N. Asada for assistance, and A. Mizokami and M. Imaizumi for secretarial assistance. This work was supported in part by grants from the Ministry of Education, Science, Sports, Culture and Technology of Japan.

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T. Nakamura and T. Nakano conceived the project and wrote the manuscript. T. Nakamura designed and performed the all experiments and evaluated the results. Y.-J.L., H.N. and H.U. propagated PGC7−/− mice. K.I., S.M. and A.O. performed some of the experiments. M.T. and Y.S. provided G9a−/− ES cells and related materials.

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Correspondence to Toshinobu Nakamura or Toru Nakano.

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The authors declare no competing financial interests.

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This file contains a Supplementary Discussion, Supplementary References, Supplementary Figures 1-22 and Supplementary Tables 1-2. (PDF 7551 kb)

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Nakamura, T., Liu, YJ., Nakashima, H. et al. PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos. Nature 486, 415–419 (2012). https://doi.org/10.1038/nature11093

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