The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5′ → 3′ direction.
CpG islands are regions of DNA characterized by a high frequency of cytosine-guanine (CpG) dinucleotides.
These regions are often found near gene promoter sites in the genome.
CpG islands play a crucial role in the regulation of gene expression.
Methylation of CpG islands can influence gene expression by affecting the binding of transcription factors to DNA.
Hypermethylation of CpG islands is associated with gene silencing, where the gene is less likely to be transcribed.
Hypomethylation of CpG islands can lead to increased gene expression.
CpG islands are important in various biological processes, including development, differentiation, and disease.
Aberrant methylation of CpG islands has been implicated in conditions such as cancer and other diseases.
CpG sites occur with high frequency in genomic regions called CpG islands.
Cytosines in CpG dinucleotides can be methylated to form 5-methylcytosines.
Enzymes that add a methyl group are called DNA methyltransferases.
70% to 80% of CpG cytosines are methylated.
Methylating the cytosine within a gene can change its expression, a mechanism that is part of gene regulation that is called epigenetics.
Methylated cytosines often mutate to thymines.
In humans, about 70% of promoters located near the transcription start site of a gene contain a CpG island.
CpG is shorthand for 5’—C—phosphate—G—3′ , that is, cytosine and guanine separated by only one phosphate group; phosphate links any two nucleosides together in DNA.
The frequency of CpG dinucleotides in human genomes is less than one-fifth of the expected frequency, a consequence of the high mutation rate of methylated CpG site.
The C to T transition rate at methylated CpG sites is ~10 fold higher than at unmethylated sites.
There are 28,890 CpG islands in the human genome, (50,267 if one includes CpG islands in repeat sequences).
Since CpG islands contain multiple CpG dinucleotide sequences, there appear to be more than 20 million CpG dinucleotides in the human genome.
Many genes genomes have CpG islands associated with the start of the gene (promoter regions).
The presence of a CpG island is used to help in the prediction and annotation of genes.
CpG islands are typically 300–3,000 base pairs in length, and have been found in or near approximately 40% of promoters of mammalian genes.
Over 60% of human genes and almost all house-keeping genes have their promoters embedded in CpG islands.
CpG islands typically occur at or near the transcription start site of genes, particularly housekeeping genes: about 70% of promoters located near the transcription start site of a gene (proximal promoters) contain a CpG island.
Distal promoter elements also frequently contain CpG islands.
CpG islands also occur frequently in promoters for functional noncoding RNAs such as microRNAs.
Methylation of CpG islands silences genes.
In cancers, loss of expression of genes occurs about 10 times more frequently by hypermethylation of promoter CpG islands than by mutations.
Hypomethylation of CpG islands in promoters results in overexpression of the genes or gene sets affected.
In cancers, promoter CpG hyper/hypo-methylation of genes and of microRNAs causes loss of expression, or sometimes increased expression, of far more genes than does mutation.
DNA repair genes are frequently repressed in cancers due to hypermethylation of CpG islands within their promoters.
Many types of cancer are deficient in one or more DNA repair genes due to hypermethylation of their promoters.
Promoter hypermethylation of the DNA repair gene MGMT occurs in 93% of bladder cancers, 88% of stomach cancers, 74% of thyroid cancers, 40%-90% of colorectal cancers and 50% of brain cancers.
Promoter hypermethylation of LIG4 occurs in 82% of colorectal cancers.
Promoter hypermethylation of NEIL1 occurs in 62% of head and neck cancers and in 42% of non-small-cell lung cancers.
Promoter hypermethylation of ATM occurs in 47% of non-small-cell lung cancers.
Promoter hypermethylation of MLH1 occurs in 48% of non-small-cell lung cancer squamous cell carcinomas.
Promoter hypermethylation of FANCB occurs in 46% of head and neck cancers.
The promoters of two genes, PARP1 and FEN1, are hypomethylated and these genes are over-expressed in numerous cancers.
PARP1 and FEN1 are essential genes in the error-prone and mutagenic DNA repair pathway: If this pathway is over-expressed the excess mutations it causes can lead to cancer.
PARP1 is over-expressed in tyrosine kinase-activated leukemias, in neuroblastoma, in testicular and other germ cell tumors, and in Ewing’s sarcoma.
FEN1 is over-expressed in the majority of cancers of the breast, prostate, stomach, neuroblastomas, pancreatic, and lung.
DNA damage appears to be the primary underlying cause of cancer, and If accurate DNA repair is deficient, DNA damages tend to accumulate.
Excess DNA damage can increase mutational errors during DNA replication due to error-prone translesion synthesis, and can also increase epigenetic alterations due to errors during DNA repair.
Such mutations and epigenetic alterations can give rise malignancies.
CpG island hyper/hypo-methylation in the promoters of DNA repair genes are likely central to progression to cancer.
Age has a strong effect on DNA methylation levels on tens of thousands of CpG sites.
An epigenetic biological clock or DNA methylation age can be determined in humans.
Active DNA methylation and demethylation is required for memory formation and maintenance.