Intergenic, gene terminal, and intragenic CpG islands in the human genome

Medvedeva, Yulia A.; Фридман, М. В.; Oparina, N. Yu.; Malko, Dmitry B.; Ermakova, E. O.; Kulakovskiy, Ivan V.; Heinzel, Andreas; Makeev, Vsevolod J.

doi:10.1186/1471-2164-11-48

Cited by 71 publications

(62 citation statements)

References 59 publications

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“…Therefore, if selection preserves the CpG profile in coding regions of Hox genes, one would predict a significant increase of the C→G (G→C) frequency in the first case (NCC-GNN and NCG-GNN) and, on the contrary, a significant decrease of these transversions in the second case (NCC-HNN and NCG-HNN, H equals not G) compared with three other types of base substitutions. This difference is precisely what we observe for (12), and the synonymous substitution rate of CpG-containing codons is substantially reduced in regions of overlap (10,12,22). We noticed that CGIs are distributed throughout the Hox A locus and often overlap with exons.…”

Section: Excess Of Ncc-gnn↔ncg-gnn Transversions In Hox Coding Regionssupporting

confidence: 62%

“…Most HCG promoters are not methylated in somatic cells and, although experimental data are limited, are commonly thought also to be unmethylated in the germ line. Being hypomethylated, these promoters and CGIs would not be subject to hypermutagenesis at CpG, thus explaining the lack of depletion over evolutionary time (22). The rate of mutation in HCG promoters is, indeed, lower than in most noncoding regions (12).…”

Section: Discussionmentioning

confidence: 99%

“…This mechanism still requires selection because the question becomes: What is preventing the methylation of these CGIs and promoters? One hypothesis is that these promoters are protected by the binding of certain protein factors such as Sp1 (22) or Cfp1 (33). However, most coding regions that are associated with HCG promoters are not protected from CpG depletion, so something must be different about the coding regions of high-CpG norm genes.…”

Section: Discussionmentioning

confidence: 99%

“…First, recent genome-wide methylation studies revealed a positive correlation between transcription levels and gene-body methylation levels (2,10,14,25). Second, by comparing M. musculus and H. sapiens genomes, Medvedeva et al (22) found that the synonymous substitution rate of CpG-containing codons is substantially reduced where protein-coding exons overlap CGIs. Third, the sea squirt Ciona intestinalis has a genome about equally divided between methylated and unmethylated domains, with most gene bodies in the methylated domain (10).…”

Section: Discussionmentioning

confidence: 99%

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CpG island clusters and pro-epigenetic selection for CpGs in protein-coding exons of HOX and other transcription factors

Branciamore¹,

Chen

Riggs

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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CpG dinucleotides contribute to epigenetic mechanisms by being the only site for DNA methylation in mammalian somatic cells. They are also mutation hotspots and ∼5-fold depleted genomewide. We report here a study focused on CpG sites in the coding regions of Hox and other transcription factor genes, comparing methylated genomes of Homo sapiens, Mus musculus, and Danio rerio with nonmethylated genomes of Drosophila melanogaster and Caenorhabditis elegans. We analyzed 4-fold degenerate, synonymous codons with the potential for CpG. That is, we studied "silent" changes that do not affect protein products but could damage epigenetic marking. We find that DNA-binding transcription factors and other developmentally relevant genes show, only in methylated genomes, a bimodal distribution of CpG usage. Several genetic code-based tests indicate, again for methylated genomes only, that the frequency of silent CpGs in Hox genes is much greater than expectation. Also informative are NCG-GNN and NCC-GNN codon doublets, for which an unusually high rate of G to C and C to G transversions was observed at the third (silent) position of the first codon. Together these results are interpreted as evidence for strong "pro-epigenetic" selection acting to preserve CpG sites in coding regions of many genes controlling development. We also report that DNA-binding transcription factors and developmentally important genes are dramatically overrepresented in or near clusters of three or more CpG islands, suggesting a possible relationship between evolutionary preservation of CpG dinucleotides in both coding regions and CpG islands.DNA methylation | epigenetics | evolution | gene duplication C pG dinucleotides are of special interest for several reasons. In somatic cells of mammals and other vertebrates, cytosine DNA methylation is almost entirely in CpGs (1, 2) and is an epigenetic mechanism essential for normal development (3, 4). The C in CpGs is highly mutable, with C to T (and complementary G to A) transitions being the most common mutations. The ≈30-fold increased mutation rate for CpG is generally thought to be due to the enzymatic methylation of CpGs, with the formation of 5-methylcytosine ( m C). Deamination of m C then leads to enhanced mutagenesis (5, 6). Most likely for this reason the frequency of CpGs in the mammalian genome is on average ∼5-fold below expectation based on genome-wide nucleotide composition. Importantly, some regions of the genome are not depleted of CpGs and, if >200 bp, are called CpG islands (CGIs) (7,8). As a hallmark feature, CGIs are usually unmethylated. However, some CGIs show tissue-specific methylation, and much evidence indicates that methylated CpG sites ( m CpG) in promoters, enhancers, and other regulatory regions do play an essential role in embryonic development, gene imprinting, and X chromosome inactivation (3, 9, 10). For the above reasons there have been numerous studies of CpGs in promoters (11,12). Over 50% of promoters are in CGIs and there is a strong inverse correlation, especially in c...

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Section: Excess Of Ncc-gnn↔ncg-gnn Transversions In Hox Coding Regionssupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

CpG island clusters and pro-epigenetic selection for CpGs in protein-coding exons of HOX and other transcription factors

Branciamore¹,

Chen

Riggs

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Approximately 67% of these CGIs overlap with UCSC genes, and they can be separated into three subgroups according to their relative position to genes, i.e., the 5′-(first exon/ promoter overlapping), the intragenic, and the 3′-(last exon overlapping) CGIs. Most gene body CGIs belong to the 5′-CGI subgroup, which are present in virtually all housekeeping genes (61,62).…”

Section: Dna Methylation and A Cytosine-phosphateguanine Islandmentioning

confidence: 99%

Epigenetic considerations of the APOE gene

Foraker

2015

Biomolecular Concepts

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Abstract:The apolipoprotein E (APOE) gene is robustly linked with numerous physiological conditions, including healthy aging, altered cardiovascular fitness, and cognitive function. These connections have been established primarily by phenotype-genotype association studies using APOE's three common genetic variants (ε2, ε3, and ε4). These variants encode for the three apoE protein isoforms (E2, E3, and E4), which have slightly different structures and, consequently, distinct functions in lipid metabolism. However, the differential lipid binding and transferring properties of these isoforms cannot fully explain the association of APOE with such a wide range of physiological phenotypes. One potential explanation for APOE's pleiotropic roles may lie in its unique epigenetic properties. In this article, we present a brief review of the APOE gene and protein, its disease associations, and epigenetic components, with a focus on DNA methylation. We close with a discussion of the prospective epigenetic implications of APOE in disease.

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Epigenetic changes in the CDKN2A locus are associated with differential expression of P16INK4A and P14ARF in HPV‐positive oropharyngeal squamous cell carcinoma

et al. 2015

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Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is recognized as a distinct disease entity associated with improved survival. DNA hypermethylation profiles differ significantly by HPV status suggesting that a specific subset of methylated CpG loci could give mechanistic insight into HPV-driven OPSCC. We analyzed genome-wide DNA methylation of primary tumor samples and adjacent normal mucosa from 46 OPSCC patients undergoing treatment at Montefiore Medical Center, Bronx, NY using the Illumina HumanMethylation27 beadchip. For each matched tissue set, we measured differentially methylated CpG loci using a change in methylation level (M value). From these analyses, we identified a 22 CpG loci panel for HPV+ OPSCC that included four CDKN2A loci downstream of the p16(INK4A) and p14(ARF) transcription start sites. This panel was significantly associated with overall HPV detection (P < 0.05; ROC area under the curve = 0.96, 95% CI: 0.91–1.0) similar to the subset of four CDKN2A-specific CpG loci (0.90, 95% CI: 0.82–0.99) with equivalence to the full 22 CpG panel. DNA hypermethylation correlated with a significant increase in alternative open reading frame (ARF) expression in HPV+ OPSCC primary tumors, but not to the other transcript variant encoded by the CDKN2A locus. Overall, this study provides evidence of epigenetic changes to the downstream region of the CDKN2A locus in HPV+ oropharyngeal cancer that are associated with changes in expression of the coded protein products.

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Intergenic, gene terminal, and intragenic CpG islands in the human genome

Cited by 71 publications

References 59 publications

CpG island clusters and pro-epigenetic selection for CpGs in protein-coding exons of HOX and other transcription factors

CpG island clusters and pro-epigenetic selection for CpGs in protein-coding exons of HOX and other transcription factors

Epigenetic considerations of the APOE gene

Epigenetic changes in the CDKN2A locus are associated with differential expression of P16INK4A and P14ARF in HPV‐positive oropharyngeal squamous cell carcinoma

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