Abstract
CpG islands often exhibit low DNA methylation, high histone H3 lysine 4 trimethylation, low nucleosome density, and high DNase I hypersensitivity, yet the rules by which CpG islands are sensed remain poorly understood. In this study, we first evaluated the relationships between the DNA and the chromatin properties of CpG islands in embryonic stem cells using modified bacterial artificial chromosomes. Then, using a bioinformatic approach, we identified strict CpG-island density and length thresholds in mouse embryonic stem and differentiated cells that consistently specify low DNA methylation levels. Surprisingly, the human genome exhibited a dramatically different relationship between DNA properties and DNA methylation levels of CpG islands. Further analysis allowed speculation that this difference is accommodated in part by evolutionary changes in the nucleotide composition of orthologous promoters. Thus, a change in the rules by which CpG-island properties are sensed may have co-evolved with compensatory genome adaptation events during mammalian evolution.