Article abstract
Nature Genetics 39, 457 - 466 (2007)
Published online: 4 March 2007 | doi:10.1038/ng1990
Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome
Michael Weber1, Ines Hellmann2,3, Michael B Stadler1, Liliana Ramos4, Svante Pääbo2, Michael Rebhan1 & Dirk Schübeler1
Abstract
To gain insight into the function of DNA methylation at cis-regulatory regions and its impact on gene expression, we measured methylation, RNA polymerase occupancy and histone modifications at 16,000 promoters in primary human somatic and germline cells. We find CpG-poor promoters hypermethylated in somatic cells, which does not preclude their activity. This methylation is present in male gametes and results in evolutionary loss of CpG dinucleotides, as measured by divergence between humans and primates. In contrast, strong CpG island promoters are mostly unmethylated, even when inactive. Weak CpG island promoters are distinct, as they are preferential targets for de novo methylation in somatic cells. Notably, most germline-specific genes are methylated in somatic cells, suggesting additional functional selection. These results show that promoter sequence and gene function are major predictors of promoter methylation states. Moreover, we observe that inactive unmethylated CpG island promoters show elevated levels of dimethylation of Lys4 of histone H3, suggesting that this chromatin mark may protect DNA from methylation.
- Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
- Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, D-04103 Leipzig, Germany.
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University of Copenhagen, Universitetsparken 15, Copenhagen
, Denmark, 2100. - Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
Correspondence to: Dirk Schübeler1 e-mail: dirk@fmi.ch
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