CpG site - Knowledge

1008: 1047: 1166:(TEs) where TEs are not only responsible in the genome expansion but also CpG loss in a host DNA. TEs can be known as "methylation centers" whereby the methylation process, the TEs spreads into the flanking DNA once in the host DNA. This spreading might subsequently result in CpG loss over evolutionary time. Older evolutionary times show a higher CpG loss in the flanking DNA, compared to the younger evolutionary times. Therefore, the DNA methylation can lead eventually to the noticeably loss of CpG sites in neighboring DNA. 578:, or TDG) that specifically replaces T's from T/G mismatches. However, due to the rarity of CpGs, it is theorised to be insufficiently effective in preventing a possibly rapid mutation of the dinucleotides. The existence of CpG islands is usually explained by the existence of selective forces for relatively high CpG content, or low levels of methylation in that genomic area, perhaps having to do with the regulation of gene expression. A 2011 study showed that most CpG islands are a result of non-selective forces. 330: 675:

protein coding genes, suggesting that about 867 genes in a colon tumor have lost expression due to CpG island methylation. A separate study found an average of 1,549 differentially methylated regions (hypermethylated or hypomethylated) in the genomes of six colon cancers (compared to adjacent mucosa), of which 629 were in known promoter regions of genes. A third study found more than 2,000 genes differentially methylated between colon cancers and adjacent mucosa. Using

587: 4246: 1175: 38: 566:, in vertebrates. A C (cytosine) base followed immediately by a G (guanine) base (a CpG) is rare in vertebrate DNA because the cytosines in such an arrangement tend to be methylated. This methylation helps distinguish the newly synthesized DNA strand from the parent strand, which aids in the final stages of DNA proofreading after duplication. However, over time methylated cytosines tend to turn into 290: 283: 1193:

the insertion into a host DNA can produce DNA methylation and provoke a spreading into the Flanking DNA area. This spreading is why there are is considerable CpG loss and genome expansion. However, this is a result that is analyzed over time because older Alus elements show more CpG loss in sites of neighboring DNA compared to younger ones.

535:. Based on an extensive search on the complete sequences of human chromosomes 21 and 22, DNA regions greater than 500 bp were found more likely to be the "true" CpG islands associated with the 5' regions of genes if they had a GC content greater than 55%, and an observed-to-expected CpG ratio of 65%. 1178:

CpG methylation contributes to the genome expansion and consequently to CpG depletion. This picture shows a genome with no TEs and unmethylated CpG sites, and the insertion and transposition of a TE lead to methylation and silencing of the TE. Through the process of CpG methylation a decrease in CpG

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neurons were differentially methylated. However while the hippocampus is essential for learning new information it does not store information itself. In the mouse experiments of Halder, 1,206 differentially methylated genes were seen in the hippocampus one hour after contextual fear conditioning but

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et al. since the Venter et al. genome sequence did not include the interiors of highly similar repetitive elements and the extremely dense repeat regions near the centromeres. Since CpG islands contain multiple CpG dinucleotide sequences, there appear to be more than 20 million CpG dinucleotides in

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Alu elements are known as the most abundant type of transposable elements. Some studies have used Alu elements as a way to study the factors responsible for genome expansion. Alu elements are CpG-rich in a longer amount of sequence, unlike LINEs and ERVs. Alus can work as a methylation center, and

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One 2012 study listed 147 specific genes with colon cancer-associated hypermethylated promoters, along with the frequency with which these hypermethylations were found in colon cancers. At least 10 of those genes had hypermethylated promoters in nearly 100% of colon cancers. They also indicated 11

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or passenger mutations. In contrast, in one study of colon tumors compared to adjacent normal-appearing colonic mucosa, 1,734 CpG islands were heavily methylated in tumors whereas these CpG islands were not methylated in the adjacent mucosa. Half of the CpG islands were in promoters of annotated

657:. The presence of multiple methylated CpG sites in CpG islands of promoters causes stable silencing of genes. Silencing of a gene may be initiated by other mechanisms, but this is often followed by methylation of CpG sites in the promoter CpG island to cause the stable silencing of the gene. 1183:

There is generally an inverse correlation between genome size and number of CpG islands, as larger genomes typically have a greater number of transposable elements. Selective pressure against TE's is substantially reduced if expression is suppressed via methylation, further TE's can act as

1184:"methylation centres" facilitating methylation of flanking DNA. Since methylation reduces selective pressure on nucleotide sequence long term methylation of CpG sites increases accumulation of spontaneous cytosine to thymine transitions, thereby resulting in a loss of Cp sites. 959:

to DNA bases) exhibit a sequence preference for cytosines within CpG sites. In the mouse brain, 4.2% of all cytosines are methylated, primarily in the context of CpG sites, forming 5mCpG. Most hypermethylated 5mCpG sites increase the repression of associated genes.

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CpG dinucleotides frequently occur in CpG islands (see definition of CpG islands, below). There are 28,890 CpG islands in the human genome, (50,267 if one includes CpG islands in repeat sequences). This is in agreement with the 28,519 CpG islands found by

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How methylation of CpG sites followed by spontaneous deamination leads to a lack of CpG sites in methylated DNA. As a result, residual CpG islands are created in areas where methylation is rare, and CpG sites stick (or where C to T mutation is highly

45:, the " 5'—C—phosphate—G—3' " sequence of nucleotides, is indicated on one DNA strand (in yellow). On the reverse DNA strand (in blue), the complementary 5'—CpG—3' site is shown. A C-G base-pairing between the two DNA strands is also indicated (right) 508: 695:

to direct post-transcriptional repression. On average, each microRNA represses several hundred target genes. Thus microRNAs with hypermethylated promoters may be allowing over-expression of hundreds to thousands of genes in a cancer.

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these altered methylations were reversed and not seen after four weeks. In contrast with the absence of long-term CpG methylation changes in the hippocampus, substantial differential CpG methylation could be detected in

2807:"Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix" 111:. In mammals, 70% to 80% of CpG cytosines are methylated. Methylating the cytosine within a gene can change its expression, a mechanism that is part of a larger field of science studying gene regulation that is called 538:

CpG islands are characterized by CpG dinucleotide content of at least 60% of that which would be statistically expected (~4–6%), whereas the rest of the genome has much lower CpG frequency (~1%), a phenomenon called

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CpG dinucleotides have long been observed to occur with a much lower frequency in the sequence of vertebrate genomes than would be expected due to random chance. For example, in the human genome, which has a 42%

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The information above shows that, 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.

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In cancers, loss of expression of genes occurs about 10 times more frequently by hypermethylation of promoter CpG islands than by mutations. For example, in a colorectal cancer there are usually about 3 to 6

559:. Most of the methylation differences between tissues, or between normal and cancer samples, occur a short distance from the CpG islands (at "CpG island shores") rather than in the islands themselves. 777:. About seventeen types of cancer are frequently deficient in one or more DNA repair genes due to hypermethylation of their promoters. As an example, promoter hypermethylation of the DNA repair gene 990:) and the expression of 564 genes was up-regulated (often associated with hypomethylation of CpG sites in gene promoters). At 24 hours after training, 9.2% of the genes in the rat genome of 1151:, allowing TET1 to oxidize the 5mC adjacent to 8-OHdG, as shown in the first figure in this section. This initiates the demethylation pathway shown in the second figure in this section. 383: 345:, a GC percentage greater than 50%, and an observed-to-expected CpG ratio greater than 60%. The "observed-to-expected CpG ratio" can be derived where the observed is calculated as: 231: 341:(or CG islands) are regions with a high frequency of CpG sites. Though objective definitions for CpG islands are limited, the usual formal definition is a region with at least 200 3038:

Newman RE, Soldatenkov VA, Dritschilo A, Notario V (2002). "Poly(ADP-ribose) polymerase turnover alterations do not contribute to PARP overexpression in Ewing's sarcoma cells".

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whose promoters were hypermethylated in colon cancers at frequencies between 50% and 100% of cancers. MicroRNAs (miRNAs) are small endogenous RNAs that pair with sequences in

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neurons during memory maintenance. There were 1,223 differentially methylated genes in the anterior cingulate cortex of mice four weeks after contextual fear conditioning.

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DNA damage appears to be the primary underlying cause of cancer. If accurate DNA repair is deficient, DNA damages tend to accumulate. Such excess DNA damage can increase

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have their promoters embedded in CpG islands. Given the frequency of GC two-nucleotide sequences, the number of CpG dinucleotides is much lower than would be expected.

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Zhou X, Zhuang Z, Wang W, He L, Wu H, Cao Y, Pan F, Zhao J, Hu Z, Sekhar C, Guo Z (September 2016). "OGG1 is essential in oxidative stress induced DNA demethylation".

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As reviewed by Duke et al., neuron DNA methylation (repressing expression of particular genes) is altered by neuronal activity. Neuron DNA methylation is required for

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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

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were hypermethylated and 369 were hypomethylated in cancers. Hypomethylation of CpG islands in promoters results in overexpression of the genes or gene sets affected.

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of a gene, in most instances the CpG sites in the CpG islands of promoters are unmethylated if the genes are expressed. This observation led to the speculation that

440: 1086:). In an alternative oxidative deamination pathway, 5hmC can be oxidatively deaminated by activity-induced cytidine deaminase/apolipoprotein B mRNA editing complex 1154:

Altered protein expression in neurons, controlled by ROS-dependent demethylation of CpG sites in gene promoters within neuron DNA, is central to memory formation.

388: 1383:; Linton, Lauren M.; Birren, Bruce; Nusbaum, Chad; Zody, Michael C.; Baldwin, Jennifer; Devon, Keri; Dewar, Ken; Doyle, Michael (15 February 2001). 3175:"Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells" 2907:"c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase-Activated Leukemias" 2141: 864:

is over-expressed in tyrosine kinase-activated leukemias, in neuroblastoma, in testicular and other germ cell tumors, and in Ewing's sarcoma,

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is a key enzyme involved in demethylating 5mCpG. However, TET1 is only able to act on 5mCpG if an ROS has first acted on the guanine to form

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of thousands of CpG sites during memory formation depends on initiation by ROS. In 2016, Zhou et al., showed that ROS have a central role in

248:, and the resulting G:T mismatched bases are often improperly resolved to A:T; whereas the deamination of unmethylated cytosine results in a 520:

In mammalian genomes, CpG islands are typically 300–3,000 base pairs in length, and have been found in or near approximately 40% of

3452:"Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island" 3425:

Bernstein, C; Prasad, AR; Nfonsam, V; Bernstein, H. (2013). "Chapter 16: DNA Damage, DNA Repair and Cancer". In Chen, Clark (ed.).

2056:"Footprinting of mammalian promoters: use of a CpG DNA methyltransferase revealing nucleosome positions at a single molecule level" 1074:(5hmC). In successive steps TET enzymes further hydroxylate 5hmC to generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). 754: 726: 2995:

Mego M, Cierna Z, Svetlovska D, Macak D, Machalekova K, Miskovska V, et al. (2013). "PARP expression in germ cell tumours".

779: 746: 3216:"Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis" 170: 3434: 2871: 2410: 2117: 2038: 967:; is modified by experiences; and active DNA methylation and demethylation is required for memory formation and maintenance. 895:). Thus, CpG island hyper/hypo-methylation in the promoters of DNA repair genes are likely central to progression to cancer. 653:

In humans, DNA methylation occurs at the 5 position of the pyrimidine ring of the cytosine residues within CpG sites to form

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of cytosine and guanine for double-stranded sequences. The CpG notation is therefore to be interpreted as the cytosine being

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Since age has a strong effect on DNA methylation levels on tens of thousands of CpG sites, one can define a highly accurate

2254:"The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores" 1523:"Bayesian Markov chain Monte Carlo sequence analysis reveals varying neutral substitution patterns in mammalian evolution" 1139:(8-OHdG), resulting in a 5mCp-8-OHdG dinucleotide (see first figure in this section). After formation of 5mCp-8-OHdG, the 857: 708:

DNA repair genes are frequently repressed in cancers due to hypermethylation of CpG islands within their promoters. In

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Kaur S, Lotsari-Salomaa JE, Seppänen-Kaijansinkko R, Peltomäki P (2016). "MicroRNA Methylation in Colorectal Cancer".

181:, the latter meaning that a guanine is followed by a cytosine in the 5' → 3' direction of a single-stranded sequence. 4158: 1597: 1058:

As reviewed in 2018, in brain neurons, 5mC is oxidized by the ten-eleven translocation (TET) family of dioxygenases (

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is over-expressed in the majority of cancers of the breast, prostate, stomach, neuroblastomas, pancreatic, and lung.

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of the time. The frequency of CpG dinucleotides in human genomes is less than one-fifth of the expected frequency.

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targets 8-OHdG and binds to the lesion without immediate excision. OGG1, present at a 5mCp-8-OHdG site recruits

3256: 3130:(2006). "Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score". 2544:

Illingworth RS, Gruenewald-Schneider U, Webb S, Kerr AR, James KD, Turner DJ, Smith C, Harrison DJ, Andrews R,

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Field, Adam E.; Robertson, Neil A.; Wang, Tina; Havas, Aaron; Ideker, Trey; Adams, Peter D. (September 2018).

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of the APRT gene are indicated (blue), and the start (ATG) and stop (TGA) codons are emphasized (bold blue).

517:). Because of this, the presence of a CpG island is used to help in the prediction and annotation of genes. 201: 2107: 531:

A 2002 study revised the rules of CpG island prediction to exclude other GC-rich genomic sequences such as

3595:"Toll-like receptor 9-dependent immune activation by unmethylated CpG motifs in Aspergillus fumigatus DNA" 1147:

binds to the 8-OHdG lesion without immediate excision. Adherence of OGG1 to the 5mCp-8-OHdG site recruits

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In 2016 Halder et al. using mice, and in 2017 Duke et al. using rats, subjected the rodents to contextual

4266: 2249: 928: 3386:"DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture" 887:

alterations due to errors during DNA repair. Such mutations and epigenetic alterations can give rise to

4236: 1136: 1028: 17: 2305:"Primate CpG Islands Are Maintained by Heterogeneous Evolutionary Regimes Involving Minimal Selection" 638: 996: 3354:

Nikolova T, Christmann M, Kaina B (2009). "FEN1 is overexpressed in testis, lung and brain tumors".

3307:"Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays" 1627: 1094:(Thy). 5hmU can be cleaved by TDG, single-strand-selective monofunctional uracil-DNA glycosylase 1 ( 3890:"The Role of Activity-Dependent DNA Demethylation in the Adult Brain and in Neurological Disorders" 2805:

Rieke DT, Ochsenreither S, Klinghammer K, Seiwert TY, Klauschen F, Tinhofer I, et al. (2016).

1208: 912: 904: 610: 127: 28: 1027:-pG, or 5mCpG. Reactive oxygen species (ROS) may attack guanine at the dinucleotide site, forming 1227:

Jabbari K, Bernardi G (May 2004). "Cytosine methylation and CpG, TpG (CpA) and TpA frequencies".

1114: 1075: 1071: 630: 575: 3644:"Genomic distribution and inter-sample variation of non-CpG methylation across human cell types" 2905:

Muvarak N, Kelley S, Robert C, Baer MR, Perrotti D, Gambacorti-Passerini C, et al. (2015).

1106:). AP sites and T:G mismatches are then repaired by base excision repair (BER) enzymes to yield 1007: 982:

brain region of rats, the expression of 1,048 genes was down-regulated (usually associated with

3801:"DNA methylation changes in plasticity genes accompany the formation and maintenance of memory" 3593:

Ramirez-Ortiz ZG, Specht CA, Wang JP, Lee CK, Bartholomeu DC, Gazzinelli RT, Levitz SM (2008).

1144: 1036: 503:{\displaystyle (({\text{number of }}C+{\text{number of }}G)/2)^{2}/{\text{length of sequence}}} 3990:"Reactive Oxygen Species: Physiological and Physiopathological Effects on Synaptic Plasticity" 4152: 2214:

Feil R, Berger F (2007). "Convergent evolution of genomic imprinting in plants and mammals".

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In adult somatic cells DNA methylation typically occurs in the context of CpG dinucleotides (

952: 880: 629:, where the CpG island-containing element is located about 5,400 nucleotides upstream of the 257: 108: 3799:

Halder R, Hennion M, Vidal RO, Shomroni O, Rahman RU, Rajput A, et al. (January 2016).

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Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C, et al. (2003).

3075:"Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers" 551:

of CpG sites in the promoter of a gene may inhibit gene expression. Methylation, along with

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CpG islands typically occur at or near the transcription start site of genes, particularly

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Beggs AD, Jones A, El-Bahrawy M, El-Bahwary M, Abulafi M, Hodgson SV, et al. (2013).

2354:"Role of ERCC1 promoter hypermethylation in drug resistance to cisplatin in human gliomas" 8: 1518: 987: 964: 936: 680: 676: 671: 606: 514: 123: 4189: 4108: 3255:

Krause A, Combaret V, Iacono I, Lacroix B, Compagnon C, Bergeron C, et al. (2005).

2956:"Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma" 2501: 2172: 1979: 1880: 1820: 1754: 1711: 1694: 1538: 1467: 1400: 1282: 1113:

Two reviews summarize the large body of evidence for the critical and essential role of

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at least 15 DNA repair genes have frequently hypermethylated promoters; these genes are

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Many genes in mammalian genomes have CpG islands associated with the start of the gene (

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and TET1 oxidizes the 5mC adjacent to the 8-OHdG. This initiates demethylation of 5mC.

892: 860:. If this pathway is over-expressed the excess mutations it causes can lead to cancer. 556: 521: 430:{\displaystyle ({\text{number of }}C*{\text{number of }}G)/{\text{length of sequence}}} 3322: 3257:"Genome-wide analysis of gene expression in neuroblastomas detected by mass screening" 2191: 2156: 2030: 2023: 1899: 1864: 1557: 1522: 297:

Distribution of CpG sites (left: in red) and GpC sites (right: in green) in the human

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Jin B, Robertson KD (2013). "DNA Methyltransferases, DNA Damage Repair, and Cancer".

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Fatemi M, Pao MM, Jeong S, Gal-Yam EN, Egger G, Weisenberger DJ, et al. (2005).

2034: 2003: 1939: 1935: 1904: 1856: 1834: 1778: 1716: 1695:"Understanding what determines the frequency and pattern of human germline mutations" 1675: 1646:"Understanding what determines the frequency and pattern of human germline mutations" 1603: 1593: 1562: 1499: 1491: 1432: 1424: 1362: 1306: 1244: 1126: 1122: 1012: 971: 563: 525: 4172:

Zhou, Wanding; Liang, Gangning; Molloy, Peter L.; Jones, Peter A. (11 August 2020).

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Zhou, Wanding; Liang, Gangning; Molloy, Peter L.; Jones, Peter A. (11 August 2020).

3291: 3159: 2338: 1046: 4211: 4193: 4130: 4112: 4058: 4050: 4009: 4001: 3960: 3952: 3911: 3901: 3862: 3820: 3812: 3771: 3763: 3719: 3709: 3665: 3655: 3614: 3606: 3573: 3565: 3524: 3514: 3473: 3463: 3397: 3326: 3318: 3271: 3227: 3186: 3139: 3094: 3086: 3047: 3004: 2967: 2926: 2918: 2877: 2859: 2826: 2818: 2777: 2769: 2720: 2712: 2671: 2663: 2622: 2612: 2571: 2561: 2513: 2505: 2453: 2398: 2365: 2316: 2275: 2267: 2223: 2186: 2176: 2075: 2067: 1993: 1983: 1931: 1894: 1884: 1824: 1768: 1758: 1737:, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. (February 2001). 1706: 1665: 1657: 1585: 1552: 1542: 1481: 1471: 1414: 1404: 1352: 1344: 1296: 1286: 1236: 1051: 1024: 908: 703: 654: 590:

An image showing a hypothetical evolutionary mechanism behind CpG island formation.

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Singh P, Yang M, Dai H, Yu D, Huang Q, Tan W, Kernstine KH, Lin D, Shen B (2008).

3024: 3008: 2972: 2955: 2922: 2550:"Orphan CpG islands identify numerous conserved promoters in the mammalian genome" 1584:. Current Topics in Microbiology and Immunology. Vol. 301. pp. 283–315. 301:

gene. CpG are more abundant in the upstream region of the gene, where they form a

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Ziller MJ, Müller F, Liao J, Zhang Y, Gu H, Bock C, et al. (December 2011).

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elements also frequently contain CpG islands. An example is the DNA repair gene

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Proceedings of the National Academy of Sciences of the United States of America

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Proceedings of the National Academy of Sciences of the United States of America

3191: 3174: 2858:. Advances in Experimental Medicine and Biology. Vol. 754. pp. 3–29. 2321: 2304: 1641: 1240: 848:, were hypomethylated and these genes were over-expressed in numerous cancers. 540: 2822: 2716: 2652:"Whole-genome methylation analysis of benign and malignant colorectal tumours" 2227: 162:

notation is used to distinguish this single-stranded linear sequence from the

4260: 4207: 4126: 3941:"Reactive oxygen species in the regulation of synaptic plasticity and memory" 3906: 3123: 2127: 2103: 1589: 1495: 1428: 923:

Unmethylated CpG dinucleotide sites can be detected by Toll-like receptor 9 (

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rate at methylated CpG sites is ~10 fold higher than at unmethylated sites.

4271: 4225: 4144: 4072: 4023: 3974: 3925: 3874: 3834: 3785: 3733: 3679: 3628: 3538: 3487: 3411: 3367: 3340: 3283: 3241: 3232: 3215: 3200: 3151: 3108: 3059: 3016: 2981: 2940: 2891: 2840: 2791: 2753: 2734: 2685: 2636: 2617: 2601:"Discovery and Validation of Hypermethylated Markers for Colorectal Cancer" 2585: 2527: 2467: 2420: 2379: 2330: 2289: 2235: 2200: 2181: 2089: 2007: 1908: 1889: 1860: 1852: 1838: 1800: 1796: 1782: 1720: 1679: 1607: 1566: 1503: 1436: 1366: 1310: 1248: 1090:

deaminases to form 5-hydroxymethyluracil (5hmU) or 5mC can be converted to

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Gardiner-Garden M, Frommer M (1987). "CpG islands in vertebrate genomes".

3714: 3610: 2545: 2437: 2071: 1773: 1734: 1486: 1419: 1380: 1328: 991: 979: 884: 571: 548: 241: 112: 2252:, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P, et al. (2009). 1348: 856:

are essential genes in the error-prone and mutagenic DNA repair pathway

4005: 3554:"DNA Methylation Clocks in Aging: Categories, Causes, and Consequences" 3051: 2543: 2458: 2441: 586: 302: 195: 191: 155: 65: 4174:"DNA methylation enables transposable element-driven genome expansion" 4093:"DNA methylation enables transposable element-driven genome expansion" 3173:

Kim JM, Sohn HY, Yoon SY, Oh JH, Yang JO, Kim JH, et al. (2005).

2667: 2370: 2353: 2157:"Comprehensive analysis of CpG islands in human chromosomes 21 and 22" 1169: 198:

consisting of cytosine followed by guanine would be expected to occur

3987: 2484:, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW (2013). 1763: 1738: 1476: 1451: 1409: 1384: 1162:

CpG depletion has been observed in the process of DNA methylation of

1078:(TDG) recognizes the intermediate bases 5fC and 5caC and excises the 1020: 983: 342: 166: 151: 77: 4054: 3816: 3698:"The Crucial Role of DNA Methylation and MeCP2 in Neuronal Function" 2954:

Newman EA, Lu F, Bashllari D, Wang L, Opipari AW, Castle VP (2015).

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Region of often-methylated DNA with a cytosine followed by a guanine

4245: 3752:"Experience-dependent epigenomic reorganization in the hippocampus" 2271: 2029:(6th ed.). Mississauga: Jones & Bartlett, Canada. p. 1174: 1107: 1087: 1002: 932: 872: 688: 648: 642: 252:, which as a foreign base is quickly replaced by a cytosine by the 62: 3037: 789:

occurs in 82% of colorectal cancers. Promoter hypermethylation of

2701:"Epigenetics Offer New Horizons for Colorectal Cancer Prevention" 1091: 1083: 943:

in humans. This is used to detect intracellular viral infection.

567: 552: 245: 116: 69: 3304: 1031:(8-OHdG), and resulting in a 5mCp-8-OHdG dinucleotide site. The 704:

DNA repair genes with hyper/hypo-methylated promoters in cancers

660: 84:. CpG sites occur with high frequency in genomic regions called 37: 3424: 1580:

Walsh CP, Xu GL (2006). "Cytosine Methylation and DNA Repair".

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International Human Genome Sequencing Consortium (2001-02-15).

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Duke CG, Kennedy AJ, Gavin CF, Day JJ, Sweatt JD (July 2017).

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Cuozzo C, Porcellini A, Angrisano T, et al. (July 2007).

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Lam JS, Seligson DB, Yu H, Li A, Eeva M, Pantuck AJ, Zeng G,

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of mammalian genes. Over 60% of human genes and almost all

306: 289: 282: 3798: 3592: 3988:

Beckhauser TF, Francis-Oliveira J, De Pasquale R (2016).

3500: 3449: 2994: 2758:"Most mammalian mRNAs are conserved targets of microRNAs" 1733: 1379: 637:

gene. CpG islands also occur frequently in promoters for

58: 2248: 1187: 3551: 3353: 2904: 2747: 2698: 823:

squamous cell carcinomas. Promoter hypermethylation of

1921: 1692: 236:

This underrepresentation is a consequence of the high

150:, that is, cytosine and guanine separated by only one 4234: 3641: 2953: 2053: 1851: 1739:"Initial sequencing and analysis of the human genome" 1452:"Initial sequencing and analysis of the human genome" 1385:"Initial sequencing and analysis of the human genome" 443: 391: 351: 240:

of methylated CpG sites: the spontaneously occurring

204: 130:

of a gene (proximal promoters) contain a CpG island.

4171: 4090: 2352:

Chen HY, Shao CJ, Chen FR, Kwan AL, Chen ZP (2010).

2302: 1865:"On the sequencing and assembly of the human genome" 978:

to form. At 24 hours after the conditioning, in the

898: 3749: 2599:Wei J, Li G, Dang S, Zhou Y, Zeng K, Liu M (2016). 1915: 1170:

Genome size and CpG ratio are negatively correlated

2022: 1961: 1795: 1264: 502: 429: 377: 225: 1333:"CpG islands and the regulation of transcription" 305:, whereas GpC are more evenly distributed. The 5 185:Under-representation caused by high mutation rate 4258: 3852: 2442:"DNA methylation patterns and epigenetic memory" 2351: 1640: 1003:Demethylation at CpG sites requires ROS activity 649:Methylation of CpG islands stably silences genes 3887: 3745: 3743: 3418: 3121: 1226: 836:On the other hand, the promoters of two genes, 3072: 2539: 2537: 1957: 1955: 1953: 1322: 1320: 1260: 1258: 946: 3172: 2598: 2112:(Sixth ed.). New York, NY. p. 406. 661:Promoter CpG hyper/hypo-methylation in cancer 4030: 3981: 3938: 3932: 3881: 3792: 3740: 3695: 3374: 3347: 3298: 3248: 3207: 3166: 3115: 3031: 2988: 2947: 2898: 2853: 2847: 2798: 2741: 2692: 2643: 2592: 2474: 2386: 2345: 1845: 1789: 1727: 3691: 3689: 3450:O'Hagan HM, Mohammad HP, Baylin SB (2008). 3213: 2534: 1950: 1317: 1255: 600: 2213: 2154: 2140:: CS1 maint: location missing publisher ( 2047: 2020: 1693:Ségurel L, Wyman MJ, Przeworski M (2014). 1516: 1326: 1220: 4215: 4197: 4134: 4116: 4062: 4036: 4013: 3964: 3915: 3905: 3824: 3775: 3723: 3713: 3669: 3659: 3618: 3577: 3528: 3518: 3477: 3467: 3401: 3330: 3231: 3190: 3098: 2971: 2930: 2881: 2830: 2781: 2724: 2675: 2626: 2616: 2575: 2565: 2517: 2457: 2369: 2320: 2296: 2279: 2190: 2180: 2148: 2079: 1997: 1987: 1898: 1888: 1828: 1772: 1762: 1710: 1669: 1556: 1546: 1485: 1475: 1418: 1408: 1373: 1356: 1300: 1290: 613:of a gene (proximal promoters) contain a 582:Methylation, silencing, cancer, and aging 378:{\displaystyle ({\text{number of }}CpGs)} 3686: 2207: 1173: 1045: 1006: 585: 328: 36: 3848: 3846: 3844: 2432: 2430: 2303:Cohen N, Kenigsberg E, Tanay A (2011). 2102: 2025:Genetics: Analysis of Genes and Genomes 1579: 574:. There is a special enzyme in humans ( 263: 115:. Methylated cytosines often mutate to 14: 4259: 4039:"DNA methylation and memory formation" 3635: 3494: 3429:. BoD – Books on Demand. p. 413. 3380: 2699:Schnekenburger M, Diederich M (2012). 1962:Saxonov S, Berg P, Brutlag DL (2006). 1265:Saxonov S, Berg P, Brutlag DL (2006). 883:. Excess DNA damage can also increase 710:head and neck squamous cell carcinomas 244:of a methylated cytosine results in a 226:{\displaystyle 0.21\times 0.21=4.41\%} 133: 91:Cytosines in CpG dinucleotides can be 4086: 4084: 4082: 3443: 3427:New Research Directions in DNA Repair 3066: 2856:Epigenetic Alterations in Oncogenesis 1188:Alu elements as promoters of CpG loss 918: 3841: 2436: 2427: 2395:Non-coding RNAs in Colorectal Cancer 1205:, detector of unmethylated CpG sites 1102:), or methyl-CpG binding protein 4 ( 4037:Day JJ, Sweatt JD (November 2010). 1712:10.1146/annurev-genom-031714-125740 1082:resulting in an apyrimidinic site ( 24: 4079: 1805:"The sequence of the human genome" 858:microhomology-mediated end joining 220: 25: 4283: 1582:DNA Methylation: Basic Mechanisms 899:Methylation of CpG sites with age 4244: 3939:Massaad CA, Klann E (May 2011). 3144:10.1111/j.1464-410X.2006.06224.x 614: 288: 281: 85: 4165: 3888:Bayraktar G, Kreutz MR (2018). 3696:Fasolino M, Zhou Z (May 2017). 3586: 3545: 2242: 2096: 2014: 1098:), Nei-Like DNA Glycosylase 1 ( 974:, causing an especially strong 813:. Promoter hypermethylation of 803:. Promoter hypermethylation of 154:group; phosphate links any two 3214:Wang K, Xie C, Chen D (2014). 1686: 1634: 1573: 1510: 1443: 481: 469: 447: 444: 414: 392: 372: 352: 324: 13: 1: 4157:: CS1 maint: date and year ( 3867:10.1016/j.cellsig.2016.05.021 3403:10.1158/1541-7786.MCR-08-0020 3323:10.1016/S0002-9440(10)63911-9 3091:10.1158/1541-7786.MCR-08-0269 3009:10.1136/jclinpath-2012-201088 2973:10.1158/1541-7786.MCR-14-0337 2923:10.1158/1541-7786.MCR-14-0422 2109:Molecular biology of the cell 1214: 915:) in humans and chimpanzees. 138: 3661:10.1371/journal.pgen.1002389 3570:10.1016/j.molcel.2018.08.008 3520:10.1371/journal.pgen.0030110 3469:10.1371/journal.pgen.1000155 3276:10.1016/j.canlet.2004.10.035 2567:10.1371/journal.pgen.1001134 1936:10.1016/0022-2836(87)90689-9 1924:Journal of Molecular Biology 1869:Proc. Natl. Acad. Sci. U.S.A 1271:Proc. Natl. Acad. Sci. U.S.A 929:plasmacytoid dendritic cells 555:modification, is central to 177:should not be confused with 7: 2864:10.1007/978-1-4419-9967-2_1 2403:10.1007/978-3-319-42059-2_6 2021:Hartl DL, Jones EW (2005). 1196: 1157: 1137:8-hydroxy-2'-deoxyguanosine 1029:8-hydroxy-2'-deoxyguanosine 947:Role of CpG sites in memory 811:non-small-cell lung cancers 801:non-small-cell lung cancers 10: 4288: 3192:10.1158/1078-0432.473.11.2 2705:Curr Colorectal Cancer Rep 2486:"Cancer genome landscapes" 2322:10.1016/j.cell.2011.04.024 2155:Takai D, Jones PA (2002). 1241:10.1016/j.gene.2004.02.043 821:non-small-cell lung cancer 593: 543:. Unlike CpG sites in the 26: 2823:10.18632/oncotarget.12211 2717:10.1007/s11888-011-0116-z 2228:10.1016/j.tig.2007.02.004 937:natural killer (NK) cells 679:analysis, 569 out of 938 639:functional noncoding RNAs 296: 275: 272: 72:nucleotide in the linear 3907:10.3389/fnmol.2018.00169 1699:Annu Rev Genom Hum Genet 1590:10.1007/3-540-31390-7_11 1527:Proc Natl Acad Sci U S A 631:transcription start site 611:transcription start site 605:In humans, about 70% of 601:CpG islands in promoters 128:transcription start site 122:In humans, about 70% of 29:CpG oligodeoxynucleotide 27:Not to be confused with 4199:10.1073/pnas.1921719117 4118:10.1073/pnas.1921719117 2510:10.1126/science.1235122 1989:10.1073/pnas.0510310103 1830:10.1126/science.1058040 1548:10.1073/pnas.0404142101 1292:10.1073/pnas.0510310103 1076:Thymine-DNA glycosylase 1072:5-hydroxymethylcytosine 670:mutations and 33 to 66 576:Thymine-DNA glycosylase 570:because of spontaneous 3945:Antioxid. Redox Signal 3233:10.3892/ijmm.2014.1682 2748:Friedman RC, Farh KK, 2182:10.1073/pnas.052410099 2161:Proc Natl Acad Sci USA 1968:Proc Natl Acad Sci USA 1890:10.1073/pnas.092136699 1644:, Calabrese P (2009). 1180: 1055: 1016: 953:DNA methyltransferases 591: 504: 431: 379: 335: 256:mechanism. The C to T 227: 109:DNA methyltransferases 46: 3957:10.1089/ars.2010.3208 3768:10.1101/lm.045112.117 2774:10.1101/gr.082701.108 1177: 1164:Transposable Elements 1049: 1010: 881:translesion synthesis 831:head and neck cancers 797:head and neck cancers 589: 505: 432: 380: 332: 228: 173:to the guanine base. 158:together in DNA. The 40: 3715:10.3390/genes8050141 3611:10.1128/IAI.00047-08 2618:10.1155/2016/2192853 2106:(18 November 2014). 1141:base excision repair 1054:(5mC) in neuron DNA. 1033:base excision repair 441: 389: 385:and the expected as 349: 264:Genomic distribution 254:base excision repair 202: 148:5'—C—phosphate—G—3' 4190:2020PNAS..11719359Z 4184:(32): 19359–19366. 4109:2020PNAS..11719359Z 4103:(32): 19359–19366. 2817:(46): 75379–75393. 2502:2013Sci...339.1546V 2173:2002PNAS...99.3740T 1980:2006PNAS..103.1412S 1881:2002PNAS...99.4145M 1821:2001Sci...291.1304V 1755:2001Natur.409..860L 1539:2004PNAS..10113994H 1468:2001Natur.409..860L 1401:2001Natur.409..860L 1349:10.1101/gad.2037511 1283:2006PNAS..103.1412S 1209:DNA methylation age 965:synaptic plasticity 913:DNA methylation age 893:malignant neoplasms 879:due to error-prone 677:gene set enrichment 526:house-keeping genes 269: 134:CpG characteristics 4267:Molecular genetics 4006:10.4137/JEN.S39887 4000:(Suppl 1): 23–48. 3894:Front Mol Neurosci 3185:(2 Pt 1): 473–82. 3052:10.3892/or.9.3.529 2459:10.1101/gad.947102 2072:10.1093/nar/gni180 1533:(39): 13994–4001. 1181: 1056: 1017: 919:Unmethylated sites 592: 564:housekeeping genes 500: 497:length of sequence 427: 424:length of sequence 375: 336: 321:the human genome. 268: 223: 47: 3436:978-953-51-1114-6 2873:978-1-4419-9966-5 2668:10.1002/path.4132 2496:(6127): 1546–58. 2412:978-3-319-42057-8 2371:10.1002/ijc.24772 2119:978-0-8153-4432-2 2060:Nucleic Acids Res 2040:978-0-7637-1511-3 1815:(5507): 1304–51. 1749:(6822): 860–921. 1462:(6822): 860–921. 1395:(6822): 860–921. 1127:DNA demethylation 1123:DNA demethylation 1050:Demethylation of 1013:DNA demethylation 972:fear conditioning 829:occurs in 46% of 819:occurs in 48% of 809:occurs in 47% of 795:occurs in 62% of 655:5-methylcytosines 609:located near the 498: 464: 453: 425: 409: 398: 358: 313: 312: 146:is shorthand for 126:located near the 97:5-methylcytosines 82:5' → 3' direction 68:is followed by a 16:(Redirected from 4279: 4249: 4248: 4240: 4230: 4229: 4219: 4201: 4169: 4163: 4162: 4156: 4148: 4138: 4120: 4088: 4077: 4076: 4066: 4034: 4028: 4027: 4017: 3985: 3979: 3978: 3968: 3936: 3930: 3929: 3919: 3909: 3885: 3879: 3878: 3850: 3839: 3838: 3828: 3796: 3790: 3789: 3779: 3747: 3738: 3737: 3727: 3717: 3693: 3684: 3683: 3673: 3663: 3654:(12): e1002389. 3639: 3633: 3632: 3622: 3605:(5): 2123–2129. 3590: 3584: 3583: 3581: 3549: 3543: 3542: 3532: 3522: 3498: 3492: 3491: 3481: 3471: 3447: 3441: 3440: 3422: 3416: 3415: 3405: 3378: 3372: 3371: 3351: 3345: 3344: 3334: 3302: 3296: 3295: 3261: 3252: 3246: 3245: 3235: 3220:Int. J. Mol. Med 3211: 3205: 3204: 3194: 3179:Clin. Cancer Res 3170: 3164: 3163: 3119: 3113: 3112: 3102: 3070: 3064: 3063: 3035: 3029: 3028: 2992: 2986: 2985: 2975: 2951: 2945: 2944: 2934: 2902: 2896: 2895: 2885: 2851: 2845: 2844: 2834: 2802: 2796: 2795: 2785: 2745: 2739: 2738: 2728: 2696: 2690: 2689: 2679: 2647: 2641: 2640: 2630: 2620: 2596: 2590: 2589: 2579: 2569: 2541: 2532: 2531: 2521: 2478: 2472: 2471: 2461: 2434: 2425: 2424: 2390: 2384: 2383: 2373: 2349: 2343: 2342: 2324: 2300: 2294: 2293: 2283: 2246: 2240: 2239: 2211: 2205: 2204: 2194: 2184: 2152: 2146: 2145: 2139: 2131: 2100: 2094: 2093: 2083: 2051: 2045: 2044: 2028: 2018: 2012: 2011: 2001: 1991: 1974:(5): 1412–1417. 1959: 1948: 1947: 1919: 1913: 1912: 1902: 1892: 1849: 1843: 1842: 1832: 1793: 1787: 1786: 1776: 1766: 1764:10.1038/35057062 1731: 1725: 1724: 1714: 1690: 1684: 1683: 1673: 1638: 1632: 1631: 1625: 1621: 1619: 1611: 1577: 1571: 1570: 1560: 1550: 1514: 1508: 1507: 1489: 1479: 1477:10.1038/35057062 1447: 1441: 1440: 1422: 1412: 1410:10.1038/35057062 1377: 1371: 1370: 1360: 1324: 1315: 1314: 1304: 1294: 1262: 1253: 1252: 1224: 1052:5-Methylcytosine 1025:5-methylcytosine 976:long-term memory 909:epigenetic clock 907:(referred to as 905:biological clock 515:promoter regions 509: 507: 506: 501: 499: 496: 494: 489: 488: 476: 465: 462: 454: 451: 436: 434: 433: 428: 426: 423: 421: 410: 407: 399: 396: 384: 382: 381: 376: 359: 356: 292: 285: 270: 267: 232: 230: 229: 224: 21: 4287: 4286: 4282: 4281: 4280: 4278: 4277: 4276: 4257: 4256: 4255: 4243: 4235: 4233: 4170: 4166: 4150: 4149: 4089: 4080: 4055:10.1038/nn.2666 4049:(11): 1319–23. 4035: 4031: 3986: 3982: 3951:(10): 2013–54. 3937: 3933: 3886: 3882: 3851: 3842: 3817:10.1038/nn.4194 3797: 3793: 3748: 3741: 3694: 3687: 3640: 3636: 3591: 3587: 3550: 3546: 3499: 3495: 3462:(8): e1000155. 3448: 3444: 3437: 3423: 3419: 3390:Mol. Cancer Res 3379: 3375: 3352: 3348: 3303: 3299: 3259: 3253: 3249: 3212: 3208: 3171: 3167: 3120: 3116: 3079:Mol. Cancer Res 3071: 3067: 3036: 3032: 2997:J. Clin. Pathol 2993: 2989: 2960:Mol. Cancer Res 2952: 2948: 2911:Mol. Cancer Res 2903: 2899: 2874: 2852: 2848: 2803: 2799: 2746: 2742: 2697: 2693: 2648: 2644: 2597: 2593: 2560:(9): e1001134. 2542: 2535: 2479: 2475: 2435: 2428: 2413: 2391: 2387: 2350: 2346: 2301: 2297: 2259:Nature Genetics 2247: 2243: 2212: 2208: 2153: 2149: 2133: 2132: 2120: 2101: 2097: 2052: 2048: 2041: 2019: 2015: 1960: 1951: 1920: 1916: 1850: 1846: 1794: 1790: 1732: 1728: 1691: 1687: 1662:10.1038/nrg2529 1639: 1635: 1623: 1622: 1613: 1612: 1600: 1578: 1574: 1515: 1511: 1448: 1444: 1381:Lander, Eric S. 1378: 1374: 1343:(10): 1010–22. 1325: 1318: 1263: 1256: 1225: 1221: 1217: 1199: 1190: 1172: 1160: 1121:formation. The 1080:glycosidic bond 1005: 949: 921: 901: 877:DNA replication 706: 663: 651: 621:Distal promoter 603: 598: 596:DNA methylation 584: 495: 490: 484: 480: 472: 463:number of 461: 452:number of 450: 442: 439: 438: 422: 417: 408:number of 406: 397:number of 395: 390: 387: 386: 357:number of 355: 350: 347: 346: 327: 266: 203: 200: 199: 187: 141: 136: 57:are regions of 35: 32: 23: 22: 15: 12: 11: 5: 4285: 4275: 4274: 4269: 4254: 4253: 4232: 4231: 4164: 4078: 4029: 3994:J Exp Neurosci 3980: 3931: 3880: 3861:(9): 1163–71. 3840: 3791: 3762:(7): 278–288. 3739: 3685: 3634: 3585: 3564:(6): 882–895. 3558:Molecular Cell 3544: 3493: 3442: 3435: 3417: 3373: 3356:Anticancer Res 3346: 3317:(4): 1151–62. 3297: 3247: 3226:(5): 1268–74. 3206: 3165: 3114: 3085:(11): 1710–7. 3065: 3030: 2987: 2946: 2917:(4): 699–712. 2897: 2872: 2846: 2797: 2740: 2691: 2662:(5): 697–704. 2642: 2591: 2533: 2473: 2426: 2411: 2385: 2364:(8): 1944–54. 2358:Int. J. Cancer 2344: 2315:(5): 773–786. 2295: 2272:10.1038/ng.298 2266:(2): 178–186. 2241: 2222:(4): 192–199. 2206: 2147: 2118: 2104:Alberts, Bruce 2095: 2046: 2039: 2013: 1949: 1930:(2): 261–282. 1914: 1863:(April 2002). 1844: 1788: 1726: 1685: 1656:(7): 478–488. 1633: 1624:|journal= 1598: 1572: 1509: 1442: 1372: 1316: 1254: 1218: 1216: 1213: 1212: 1211: 1206: 1198: 1195: 1189: 1186: 1171: 1168: 1159: 1156: 1070:) to generate 1015:at a CpG site. 1011:Initiation of 1004: 1001: 988:gene promoters 948: 945: 920: 917: 900: 897: 875:errors during 799:and in 42% of 705: 702: 693:messenger RNAs 662: 659: 650: 647: 602: 599: 594:Main article: 583: 580: 541:CG suppression 493: 487: 483: 479: 475: 471: 468: 460: 457: 449: 446: 420: 416: 413: 405: 402: 394: 374: 371: 368: 365: 362: 354: 326: 323: 311: 310: 294: 293: 286: 278: 277: 274: 265: 262: 222: 219: 216: 213: 210: 207: 186: 183: 140: 137: 135: 132: 33: 9: 6: 4: 3: 2: 4284: 4273: 4270: 4268: 4265: 4264: 4262: 4252: 4247: 4242: 4241: 4238: 4227: 4223: 4218: 4213: 4209: 4205: 4200: 4195: 4191: 4187: 4183: 4179: 4175: 4168: 4160: 4154: 4146: 4142: 4137: 4132: 4128: 4124: 4119: 4114: 4110: 4106: 4102: 4098: 4094: 4087: 4085: 4083: 4074: 4070: 4065: 4060: 4056: 4052: 4048: 4044: 4043:Nat. Neurosci 4040: 4033: 4025: 4021: 4016: 4011: 4007: 4003: 3999: 3995: 3991: 3984: 3976: 3972: 3967: 3962: 3958: 3954: 3950: 3946: 3942: 3935: 3927: 3923: 3918: 3913: 3908: 3903: 3899: 3895: 3891: 3884: 3876: 3872: 3868: 3864: 3860: 3856: 3849: 3847: 3845: 3836: 3832: 3827: 3822: 3818: 3814: 3811:(1): 102–10. 3810: 3806: 3805:Nat. Neurosci 3802: 3795: 3787: 3783: 3778: 3773: 3769: 3765: 3761: 3757: 3753: 3746: 3744: 3735: 3731: 3726: 3721: 3716: 3711: 3707: 3703: 3702:Genes (Basel) 3699: 3692: 3690: 3681: 3677: 3672: 3667: 3662: 3657: 3653: 3649: 3645: 3638: 3630: 3626: 3621: 3616: 3612: 3608: 3604: 3600: 3599:Infect. Immun 3596: 3589: 3580: 3575: 3571: 3567: 3563: 3559: 3555: 3548: 3540: 3536: 3531: 3526: 3521: 3516: 3512: 3508: 3507:PLOS Genetics 3504: 3497: 3489: 3485: 3480: 3475: 3470: 3465: 3461: 3457: 3456:PLOS Genetics 3453: 3446: 3438: 3432: 3428: 3421: 3413: 3409: 3404: 3399: 3396:(4): 517–24. 3395: 3391: 3387: 3383: 3377: 3369: 3365: 3362:(7): 2453–9. 3361: 3357: 3350: 3342: 3338: 3333: 3328: 3324: 3320: 3316: 3312: 3311:Am. J. 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