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Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome.

Nature genetics

Sequence Analysis, DNA, Binding Sites, Promoter Regions, Genetic, Microarray Analysis, Humans, metabolism, Germ Cells, Genome, Human, Gene Silencing, Evolution, Molecular, DNA-Directed DNA Polymerase, DNA Methylation, CpG Islands, Chromosome Mapping, Chromatin

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      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.

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      Journal
      10.1038/ng1990
      17334365

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