CpG islands are short stretches of palindromic DNA with the sequence “CpG” that code for the same sequence in the complementary strand (i.e., repeated cytosine and guanine nucleotides with the “p” representing the linking phosphate).
CpG islands are defined as stretches of DNA 500–1500 bp long with a CG: GC ratio of more than 0.6, and they are normally found at promoters and contain the 5′ end of the transcript (reviewed in Cross and Bird, 1995).
CpG islands (CGIs) have evolved from a peculiar sequence overrepresentation of CpGs to being recognized as functionally important parts of the genome that define and regulate promoter regions of vertebrates. CGIs have been resistant to a unified mathematical definition, but recent approaches are becoming more precise in distinguishing true CGIs from artifacts such as repetitive sequences. CGIs are usually associated with lack of DNA methylation and can be considered as the best predictors for defining active or potentially active promoter regions. Methylated CGIs play a role in X-inactivation, genomic imprinting, aberrant methylation patterns in cancer, and gene silencing during cell differentiation. Most importantly, it becomes more and more evident that they are essential for fine-tuned regulatory processes by directing gene expression patterns and cell fate, thereby acting as vital landmarks of the epigenome.
Methylation of cytosines in CpG islands in promotor regions can prevent transcription factors to effectively block gene expression , and CpG islands are frequently methylated in genes that are not actively expressed.
Aberrant CpG island methylation is a common silencing mechanism in IPMNs, especially high-grade lesions. Hong et al. identified 245 genes hypermethylated in IPMNs with high-grade dysplasia compared with normal pancreatic duct samples by conducting genome-wide CpG island methylation profiling, and confirmed several genes (BNIP3, PTCHD2, SOX17, NXPH1, and EBF3) that were significantly more likely to be methylated in IPMNs with high-grade than with low-grade dysplasia by methylation-specific PCR analysis. Genes that are selectively methylated in high-grade IPMN may be used as genetic markers for malignant transformation in IPMNs.
CpG islands associated with tumor suppressor genes are unmethylated in normal tissues but often become hypermethylated during tumor formation. Growing evidence suggests that de novo methylation of CpG islands induces the silencing of associated tumor suppressor genes and may in fact be a critical step during tumor formation. The particular genes that are hypermethylated in tumor cells are strongly specific to the tissue of origin of the tumor ( Esteller et al., 2001 ). We have recently described a profile of hypermethylation among various primary human tumors ( Esteller et al., 2001a ); however, we do not currently know why some genes become hypermethylated in specific tumors and others, with similar properties (e.g., a typical CpG island), a history of loss of expression in other tumor types, and the absence of mutations remain free from methylation. We can hypothesize, as has been done previously with genetic mutations, that silencing of a particular gene may confer a survival advantage in some situations. The genes that undergo abnormal methylation in their 5′-CpG island in human cancer cover the whole spectrum of pathways involved in tumorogenesis from cell cycle and apoptosis to DNA repair and invasiveness ability. Tumor suppresor genes that contain highly methylated CpG islands in tumor cells affect cell cycle ( p16INK4a, p15INK4b, Rb, p14ARF ), DNA repair ( BRCA1, hMLH1, MGMT ), cell adherence ( CDH1, CDH13 ), apoptosis ( DAPK, TMS1 ), carcinogen metabolism ( GSTP1 ), hormonal response ( RARB2, ER ), etc. Table 8 shows the most relevant hypermethylated genes in human cancer reported so far, their function, chromosomal localization, and tumor profile ( Esteller, 2002 ).
CGIs were defined based on UCSC annotation and according to the criteria previously described [9,74]. We employed a NCBI “strict” definition for CGIs as DNA sequences (500 base windows; excluding most repetitive Alu-elements) with a GC base composition greater than 50% and a CpG observed/expected ratio of more than 0.6 [9,74]. As described by Takai and Jones [9], regions of DNA greater than 500 bp with GC composition 55% or greater and observed CpG/expected CpG of 0.65 were more likely to be associated with the 5′ regions of genes. Using this definition, 60% of RefSeq genes are found to contain one or more CGI, and 40% contain no CGI. Of the CGIs, 26,658 were covered overall, with an average of 5.63 sites each; 28,249 “north” or upstream and 25,761 “south,” or downstream CGI shores, immediately outside of the CGIs, were targeted, with averages of 2.93 and 2.81 sites, respectively. The 2-kb regions upstream and downstream of the CGI shores, referred to here as “CGI shelves,” were also targeted with a global average of 2.07 and 2.03 sites each (“North” and “South,” respectively) ( Figure 2.2B ).
A CpG island is a stretch of DNA with a high quantity of the nucleotides G and C next to one (1) another. The formal definition we use here is a stretch of DNA a minimum (at least) 200 BP long with at least 50% GC content.
for example is the DNA repair gene ERCC1, where the CpG island-containing element is located about 5,400 nucleotides upstream of the transcription start site of the ERCC1 gene . CpG island also occur frequently in promoters for functional noncoding RNAs such as microRNAs
Furthermore, the CpG sites in the CpG promoter are unmethylated because if the genes are expressed. This observation led to the speculation that CpG methylation of CpG sites in the promoter of a gene may inhibit gene expression. Methylation CpG, along with histone modification, is central to imprinting. Therefore, Most of the methylation ...
Therefore, In mammalian genomes, 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 island. Given the frequency of GC two-nucleotide sequences, ...
as a result of this, the presence of a CpG island is used to help in the prediction and annotation of genes.
Therefore, CpG should not be confused with GpC, the latter means that guanine is followed by a cytosine in the 5′ → 3′ direction of a single-stranded sequence.