This study presents genome-scale DNA methylation maps of pluripotent and differentiated cells, revealing key insights into the role of DNA methylation in development and disease. Using high-throughput reduced representation bisulphite sequencing (RRBS), the researchers generated DNA methylation profiles for mouse embryonic stem cells (ESCs), embryonic-stem-cell-derived neural precursor cells (NPCs), and eight other primary tissues. The data show that DNA methylation patterns are better correlated with histone methylation patterns than with the underlying genome sequence context. Methylation of CpGs is a dynamic epigenetic mark that changes during cellular differentiation, particularly in regulatory regions outside of core promoters. The study also identifies that 'weak' CpG islands associated with developmentally regulated genes undergo aberrant hypermethylation during extended proliferation in vitro, similar to patterns observed in some primary tumours. The results establish RRBS as a powerful technology for epigenetic profiling of cell populations relevant to developmental biology, cancer, and regenerative medicine. DNA methylation can be detected by sequencing genomic DNA treated with sodium bisulphite. RRBS allows for efficient coverage of CpG dinucleotides, with a high proportion located within CpG islands. The study also reveals that high-CpG-density promoters (HCPs) are associated with two classes of genes: housekeeping genes and key developmental genes. HCPs at housekeeping genes are enriched with H3K4me3 and are generally highly expressed, while those at developmental genes are enriched with both H3K4me3 and H3K27me3 and are generally silent. Low-CpG-density promoters (LCPs) are generally associated with tissue-specific genes. The study also shows that distal regulatory regions such as enhancers and silencers are often required for correct gene expression in mammalian cells. CpGs in regions enriched with H3K4me2 show significantly lower methylation levels than those in unenriched regions. Imprinting control regions (ICRs) are CpG-rich regulatory regions with allele-specific histone and DNA methylation. The study also shows that interspersed repeat families differ in their chromatin structure, with H3K9me3 enriched at active long terminal repeats (LTRs) and to a lesser extent at long interspersed elements (LINEs), but not at short interspersed elements (SINEs). CpGs in LTRs and LINEs are generally hypermethylated, even in CpG-rich contexts. The study further shows that the presence of H3K4 methylation and the absence of H3K9 methylation are better predictors of unmethylated CpGs than sequence context alone. The data support the notion that CpG-rich and -poor regulatory elements undergo distinct modes of epigenetic regulation. Most HCPs seem to be constitutively unmethylated and regulated by trithorax-group (trxGThis study presents genome-scale DNA methylation maps of pluripotent and differentiated cells, revealing key insights into the role of DNA methylation in development and disease. Using high-throughput reduced representation bisulphite sequencing (RRBS), the researchers generated DNA methylation profiles for mouse embryonic stem cells (ESCs), embryonic-stem-cell-derived neural precursor cells (NPCs), and eight other primary tissues. The data show that DNA methylation patterns are better correlated with histone methylation patterns than with the underlying genome sequence context. Methylation of CpGs is a dynamic epigenetic mark that changes during cellular differentiation, particularly in regulatory regions outside of core promoters. The study also identifies that 'weak' CpG islands associated with developmentally regulated genes undergo aberrant hypermethylation during extended proliferation in vitro, similar to patterns observed in some primary tumours. The results establish RRBS as a powerful technology for epigenetic profiling of cell populations relevant to developmental biology, cancer, and regenerative medicine. DNA methylation can be detected by sequencing genomic DNA treated with sodium bisulphite. RRBS allows for efficient coverage of CpG dinucleotides, with a high proportion located within CpG islands. The study also reveals that high-CpG-density promoters (HCPs) are associated with two classes of genes: housekeeping genes and key developmental genes. HCPs at housekeeping genes are enriched with H3K4me3 and are generally highly expressed, while those at developmental genes are enriched with both H3K4me3 and H3K27me3 and are generally silent. Low-CpG-density promoters (LCPs) are generally associated with tissue-specific genes. The study also shows that distal regulatory regions such as enhancers and silencers are often required for correct gene expression in mammalian cells. CpGs in regions enriched with H3K4me2 show significantly lower methylation levels than those in unenriched regions. Imprinting control regions (ICRs) are CpG-rich regulatory regions with allele-specific histone and DNA methylation. The study also shows that interspersed repeat families differ in their chromatin structure, with H3K9me3 enriched at active long terminal repeats (LTRs) and to a lesser extent at long interspersed elements (LINEs), but not at short interspersed elements (SINEs). CpGs in LTRs and LINEs are generally hypermethylated, even in CpG-rich contexts. The study further shows that the presence of H3K4 methylation and the absence of H3K9 methylation are better predictors of unmethylated CpGs than sequence context alone. The data support the notion that CpG-rich and -poor regulatory elements undergo distinct modes of epigenetic regulation. Most HCPs seem to be constitutively unmethylated and regulated by trithorax-group (trxG