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The role of DNA methylation in setting up chromatin structure during development

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Abstract

DNA methylation inhibits gene expression in animal cells, probably by affecting chromatin structure. Biochemical studies suggest that this process may be mediated by methyl-specific binding proteins that recruit enzymatic machinery capable of locally altering histone modification1. To test whether DNA methylation actually has a role in the assembly of chromatin during normal development, we used cell transfection and a transgene construct genetically programmed to be either methylated or unmethylated in all cell types of the mouse2. Chromatin immunoprecipitation (ChIP) analysis shows that the presence of DNA methylation brings about the deacetylation of histone H4 and methylation of Lys9 of histone H3 (H3 Lys9) and prevents methylation of Lys4 of histone H3 (H3 Lys4), thus generating a structure identical to that of methylated sequences in the genome. These results indicate that the methylation pattern established in early embryogenesis is profoundly important in setting up the structural profile of the genome.

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Figure 1: Programmed transgene methylation.
Figure 2: Effect of DNA methylation on histone H4 acetylation.
Figure 3: Effect of DNA methylation on histone H3 modification.
Figure 4: Effect of DNA methylation on histone H1 placement.
Figure 5: Effect of trichostatin A on reporter transgene transcription.

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Acknowledgements

We thank T. Jenuwein for his gift of branched methylated H3 Lys9 antibody. This research was supported by grants from the US National Institutes of Health, the Israel Cancer Research Fund and the Arthur and Rochelle Belfer Foundation.

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Authors and Affiliations

  1. Departments of Cellular Biochemistry & Human Genetics and Experimental Medicine and Cancer Research, P.O.B. 12272, Hebrew University, Jerusalem, 91120, Israel

    Tamar Hashimshony, Jianmin Zhang, Ilana Keshet & Howard Cedar

  2. Division of Basic Sciences, Protein Section, Laboratory of Molecular Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Michael Bustin

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  1. Tamar Hashimshony
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  2. Jianmin Zhang
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Correspondence to Howard Cedar.

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Hashimshony, T., Zhang, J., Keshet, I. et al. The role of DNA methylation in setting up chromatin structure during development. Nat Genet 34, 187–192 (2003). https://doi.org/10.1038/ng1158

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