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CG dinucleotide clustering is a species-specific property of the genome.

Glass JL, Thompson RF, Khulan B, Figueroa ME, Olivier EN, Oakley EJ, Van Zant G, Bouhassira EE, Melnick A, Golden A, Fazzari MJ, Greally JM - Nucleic Acids Res. (2007)

Bottom Line: We also show that the CG clusters co-localize in the human genome with hypomethylated loci and annotated transcription start sites to a greater extent than annotations produced by prior CpG island definitions.Moreover, this new approach allows CG clusters to be identified in a species-specific manner, revealing a degree of orthologous conservation that is not revealed by current base compositional approaches.Finally, our approach is able to identify methylating genomes (such as Takifugu rubripes) that lack CG clustering entirely, in which it is inappropriate to annotate CpG islands or CG clusters.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA, Division of Hematology/Oncology, University of Kentucky, Markey Cancer Center, 800 Rose Street, Lexington KY 40536, USA.

ABSTRACT
Cytosines at cytosine-guanine (CG) dinucleotides are the near-exclusive target of DNA methyltransferases in mammalian genomes. Spontaneous deamination of methylcytosine to thymine makes methylated cytosines unusually susceptible to mutation and consequent depletion. The loci where CG dinucleotides remain relatively enriched, presumably due to their unmethylated status during the germ cell cycle, have been referred to as CpG islands. Currently, CpG islands are solely defined by base compositional criteria, allowing annotation of any sequenced genome. Using a novel bioinformatic approach, we show that CG clusters can be identified as an inherent property of genomic sequence without imposing a base compositional a priori assumption. We also show that the CG clusters co-localize in the human genome with hypomethylated loci and annotated transcription start sites to a greater extent than annotations produced by prior CpG island definitions. Moreover, this new approach allows CG clusters to be identified in a species-specific manner, revealing a degree of orthologous conservation that is not revealed by current base compositional approaches. Finally, our approach is able to identify methylating genomes (such as Takifugu rubripes) that lack CG clustering entirely, in which it is inappropriate to annotate CpG islands or CG clusters.

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The HELP assay (13) was used on a custom promoter microarray to test cytosine methylation patterns in two samples each of CD34+ hematopoietic stem and progenitor cells (CD34) and human embryonic stem cells (ES). In panel (a) it is apparent that similar proportions of sites are categorized as hypomethylated for CG clusters (C) and CpG islands (I). However, the absolute number of hypomethylated sites detected by the CG cluster annotation is markedly larger than that for the CpG island annotation [panel (b)]. We conclude that the CG cluster annotation is not only detecting larger numbers of transcription start sites (Figure 4), it extends the ability of the CpG island annotation to identify more hypomethylated sites in the genome.
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Figure 5: The HELP assay (13) was used on a custom promoter microarray to test cytosine methylation patterns in two samples each of CD34+ hematopoietic stem and progenitor cells (CD34) and human embryonic stem cells (ES). In panel (a) it is apparent that similar proportions of sites are categorized as hypomethylated for CG clusters (C) and CpG islands (I). However, the absolute number of hypomethylated sites detected by the CG cluster annotation is markedly larger than that for the CpG island annotation [panel (b)]. We conclude that the CG cluster annotation is not only detecting larger numbers of transcription start sites (Figure 4), it extends the ability of the CpG island annotation to identify more hypomethylated sites in the genome.

Mentions: We tested the relative ability of CG clusters to detect hypomethylated sites by performing the HELP assay (12) on human embryonic stem cells and CD34+ hematopoietic stem and progenitor cells. A microarray representing HpaII-amplifiable fragments located near transcription start sites in the human genome was used for two biological replicates of each cell type. While similar proportions of loci at CpG islands and at CG clusters demonstrated hypomethylation (Figure 5a), the absolute number of hypomethylated loci differed (Figure 5b), as the hypomethylated CpG islands represent a subset of the larger group of hypomethylated CG clusters. The CG clusters identify ∼50% more hypomethylated loci than do CpG islands. We conclude that the CG cluster annotation is not only identifying more transcription start sites, it is also defining loci with comparable epigenetic characteristics.Figure 5.


CG dinucleotide clustering is a species-specific property of the genome.

Glass JL, Thompson RF, Khulan B, Figueroa ME, Olivier EN, Oakley EJ, Van Zant G, Bouhassira EE, Melnick A, Golden A, Fazzari MJ, Greally JM - Nucleic Acids Res. (2007)

The HELP assay (13) was used on a custom promoter microarray to test cytosine methylation patterns in two samples each of CD34+ hematopoietic stem and progenitor cells (CD34) and human embryonic stem cells (ES). In panel (a) it is apparent that similar proportions of sites are categorized as hypomethylated for CG clusters (C) and CpG islands (I). However, the absolute number of hypomethylated sites detected by the CG cluster annotation is markedly larger than that for the CpG island annotation [panel (b)]. We conclude that the CG cluster annotation is not only detecting larger numbers of transcription start sites (Figure 4), it extends the ability of the CpG island annotation to identify more hypomethylated sites in the genome.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2175314&req=5

Figure 5: The HELP assay (13) was used on a custom promoter microarray to test cytosine methylation patterns in two samples each of CD34+ hematopoietic stem and progenitor cells (CD34) and human embryonic stem cells (ES). In panel (a) it is apparent that similar proportions of sites are categorized as hypomethylated for CG clusters (C) and CpG islands (I). However, the absolute number of hypomethylated sites detected by the CG cluster annotation is markedly larger than that for the CpG island annotation [panel (b)]. We conclude that the CG cluster annotation is not only detecting larger numbers of transcription start sites (Figure 4), it extends the ability of the CpG island annotation to identify more hypomethylated sites in the genome.
Mentions: We tested the relative ability of CG clusters to detect hypomethylated sites by performing the HELP assay (12) on human embryonic stem cells and CD34+ hematopoietic stem and progenitor cells. A microarray representing HpaII-amplifiable fragments located near transcription start sites in the human genome was used for two biological replicates of each cell type. While similar proportions of loci at CpG islands and at CG clusters demonstrated hypomethylation (Figure 5a), the absolute number of hypomethylated loci differed (Figure 5b), as the hypomethylated CpG islands represent a subset of the larger group of hypomethylated CG clusters. The CG clusters identify ∼50% more hypomethylated loci than do CpG islands. We conclude that the CG cluster annotation is not only identifying more transcription start sites, it is also defining loci with comparable epigenetic characteristics.Figure 5.

Bottom Line: We also show that the CG clusters co-localize in the human genome with hypomethylated loci and annotated transcription start sites to a greater extent than annotations produced by prior CpG island definitions.Moreover, this new approach allows CG clusters to be identified in a species-specific manner, revealing a degree of orthologous conservation that is not revealed by current base compositional approaches.Finally, our approach is able to identify methylating genomes (such as Takifugu rubripes) that lack CG clustering entirely, in which it is inappropriate to annotate CpG islands or CG clusters.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA, Division of Hematology/Oncology, University of Kentucky, Markey Cancer Center, 800 Rose Street, Lexington KY 40536, USA.

ABSTRACT
Cytosines at cytosine-guanine (CG) dinucleotides are the near-exclusive target of DNA methyltransferases in mammalian genomes. Spontaneous deamination of methylcytosine to thymine makes methylated cytosines unusually susceptible to mutation and consequent depletion. The loci where CG dinucleotides remain relatively enriched, presumably due to their unmethylated status during the germ cell cycle, have been referred to as CpG islands. Currently, CpG islands are solely defined by base compositional criteria, allowing annotation of any sequenced genome. Using a novel bioinformatic approach, we show that CG clusters can be identified as an inherent property of genomic sequence without imposing a base compositional a priori assumption. We also show that the CG clusters co-localize in the human genome with hypomethylated loci and annotated transcription start sites to a greater extent than annotations produced by prior CpG island definitions. Moreover, this new approach allows CG clusters to be identified in a species-specific manner, revealing a degree of orthologous conservation that is not revealed by current base compositional approaches. Finally, our approach is able to identify methylating genomes (such as Takifugu rubripes) that lack CG clustering entirely, in which it is inappropriate to annotate CpG islands or CG clusters.

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