Histone modifications are thought to regulate gene expression in part by modulating DNA accessibility. Here, we measured genome-wide DNA accessibility in Drosophila melanogaster by combining M.SssI methylation footprinting with methylated DNA immunoprecipitation. We show that methylase accessibility demarcates differential distribution of active and repressive histone modifications as well as sites of transcription and replication initiation. DNA accessibility is increased at active promoters and chromosomal regions that are hyperacetylated at H4K16, particularly at the male X chromosome, suggesting that transcriptional dosage compensation is facilitated by permissive chromatin structure. Conversely, inactive chromosomal domains decorated with H3K27me3 are least accessible, supporting a model for Polycomb-mediated chromatin compaction. In addition, we detect higher accessibility at chromosomal regions that replicate early and at sites of replication initiation. Together, these findings indicate that differential histone-modification patterns and the organization of replication have distinct and measurable effects on the exposure of the DNA template.
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We thank S. Gasser, L. Ho, G.R. Crabtree and members of our laboratory for helpful comments on the manuscript, H. Angliker for Affymetrix microarray processing, D. Gaidatzis for codeveloping of the deep sequencing analysis software and I. Nissen for sample processing for deep sequencing. Illumina sequencing was carried out at the Laboratory of Quantitative Genomics, D-BSSE. O.B. and M.S. are supported by European Molecular Biology Organization long-term fellowships, M.S. and F.L. acknowledge support by a predoctoral fellowship of the Boehringer Ingelheim Fonds. Research in the laboratory of D.S. is supported by the Novartis Research Foundation, by the European Union (NoE “The Epigenome” LSHG-CT-2004-503433, LSHG-CT-2006-037415), the European Research Council (ERC-204264) and the European Molecular Biology Organization Young Investigator program.
The authors declare no competing financial interests.
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Bell, O., Schwaiger, M., Oakeley, E. et al. Accessibility of the Drosophila genome discriminates PcG repression, H4K16 acetylation and replication timing. Nat Struct Mol Biol 17, 894–900 (2010). https://doi.org/10.1038/nsmb.1825
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