CG methylation

Abstract

A striking feature of mammalian genomes is the paucity of the CG dinucleotide. There are approximately 20,000 regions termed CpG islands where CGs cluster. This represents 5% of all CGs and 1% of the genome. CpG islands are typically unmethylated and are often promoters for housekeeping genes. The remaining 95% of CG dinucleotides are disposed throughout 99% of the genome and are typically methylated and found in half of all promoters. CG methylation facilitates binding of the C/EBP family of transcription factors, proteins critical for differentiation of many tissues. This allows these proteins to localize in the methylated CG poor regions of the genome where they may produce advantageous changes in gene expression at nearby or more distant regions of the genome. In this review, our growing understanding of the consequences of CG methylation will be surveyed.

Figure 1. Chemical structure of cytosine and enrichment of CG dinucleotide

(A) Chemical structure of cytosine and methylcytosine. (B) Frequency of CG dinucleotide at a megabase scale across the mouse and Drosophila genomes shows the presence of CpG clusters, called CG islands, only in the mouse genome. Percentage of CpG dinucleotide is calculated for a 1000-bp window.

Figure 2. CG methylation status of mouse promoters

Immunoprecipitated methylated DNA is hybridized to NimbleGen promoter arrays and the average methylation for each promoter is determined. Average methylation level (in log2) is plotted against number of CG dinucleotides (in log10) for each promoter. Two distinct clusters are formed, which are demarcated by the line. One cluster consists of CG-poor promoters, where methylation increases with the CG density and they are named as methylated promoters. The second cluster consists of CG-rich promoters, where average methylation is low and they are termed as unmethylated promoters. MeDIP: Methyl CG immunoprecipitation. Reproduced from [13].

Figure 3. PhyloP scores for CREB (TGACGTCA), SP1 (CCCGCCC) and C/EBP (TTGCGCAA) canonical motifs divided into unmethylated and methylated occurrences in newborn dermal fibroblast primary cultures with a 50X methylome

The numbers in parentheses indicate the number of occurrences in the mouse genome having PhyloP score and methylation coverage. Note that the methylated sequences are less stable than the unmethylated sequences.

Figure 4. Methyl CG deamination produces new functions at methylated transcription factor binding sites elsewhere in the genome

mC: Methylated cytosine; TSS: Transcription start site.