CpG Islands and DNA Methylation


Methylated CpG dinucleotides at position 5 of cytosine are associated with transcriptional repression and an inactive chromatin conformation in mammals. CpG islands (CGI) are regions of approximately 1 kb, which colocalise with the origins of DNA replication and with the promoters of about 70% of all genes. CGIs represent approximately 1% of the genome, and the large majority of them remain nonmethylated despite their high density of CpG dinucleotides. Genomic methylation patterns are established in early embryos and are maintained during development through the interplay of demethylation mechanisms and the de novo and maintenance activities of DNA methyltransferases. The methylation signal is interpreted by proteins capable of binding methylated CpGs and of recruiting histone epigenetic modificators, transcriptional corepressors and chromatin remodellers. DNA methylation is essential for mammalian development, and abnormal methylation patterns have been found in a great variety of human tumour cells.

Key Concepts

  • Approximately 80% of CpG dinucleotides are methylated in the 5′ position of cytosine in the mammalian genome.
  • The information contained in methtylated CpGs is interpreted by proteins that specifically bind to them.
  • CpG islands represent 1% of the genome and have a high density of nonmethylated CpGs.
  • The great majority of CpG islands colocalise with transcription initiation sites and the origins of DNA replication.
  • CpG islands are differentially methylated in imprinted genes and in the inactive X chromosomes.
  • DNA methyltransferases reset the methylation patterns in early embryos and maintain their stability during development.

Keywords: CpG islands; DNA methylation; DNA methyltransferases; methylated DNA binding proteins; transcription

Figure 1. Three‐dimensional structure of a double‐stranded DNA fragment containing four methylated CpG dinucleotides. The methyl groups of the complementary methylated CpGs protrude into the major groove of the DNA molecule.
Figure 2. Examples of human genes with and without CpG islands. The diagrams show the distribution of CpGs across the 5′ end of four human genes. The α‐globin and the aldose reductase (ADO) genes are associated with CpG islands, as is clearly shown by the high density of CpG dinucleotides around their 5′ ends. In contrast, the frequency of CpGs at the 5′ ends of the β‐globin and the 5‐aminolevulinate synthase 2 (5‐ALAS) genes is similar to the genome average. Vertical lines indicate CpGs. Boxes represent exons and arrows show the transcription initiation site. Only exon 1 of the ADO and 5‐ALAS genes is shown.
Figure 3. Chromatin structure of CpG islands. The distribution of methylated and nonmethylated CpG dinucleotides is shown at the bottom (black or white circles, respectively). CGI nucleosomes (green) contain acetylated H3 and H4 histones and H3 is also methylated at lysine 4 (blue circles). CGIs lack histone H1. Nucleosomes outside CGIs (red) can be methylated at lysine 36 of H3 (red circles). Cfp1, Kdm2a and TET proteins bind to nonmethylated CpGs through their CxxC domains. CGIs are also bound by transcriptions factors (TF) and by RNA polymerase II (RNA pol II). CGIs contain a region depleted, or with low occupancy, of nucleosomes (NDR) close to the transcription initiation site.


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Further Reading

Rasmussen KD and Helin K (2016) Role of TET enzymes in DNA methylation, development, and cancer. Genes & Development 30: 733–750.

Bartolomei MS and Ferguson‐Smith AC (2011) Mammalian genomic imprinting. Cold Spring Harbor Perspectives in Biology 3: a002592.

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Du Q, Luu PL, Stirzaker C and Clark SJ (2015) Methyl‐CpG‐binding domain proteins: readers of the epigenome. Epigenomics 7: 1051–1073.

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Li E and Zhang Y (2014) DNA methylation in mammals. Cold Spring Harbor Perspectives in Biology 6: a019133.

Rasmussen KD and Helin K (2016b) Role of TET enzymes in DNA methylation, development, and cancer. Genes & Development 30: 733–750.

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Antequera, Francisco(Apr 2017) CpG Islands and DNA Methylation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005027.pub3]