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Research Article

A Novel CpG Island Set Identifies Tissue-Specific Methylation at Developmental Gene Loci

  • Robert Illingworth,

    Affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom

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  • Alastair Kerr,

    Affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom

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  • Dina DeSousa,

    Affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom

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  • Helle Jørgensen,

    Affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, London, United Kingdom

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  • Peter Ellis,

    Affiliation: Wellcome Trust Sanger Centre, Hinxton, Cambridge, United Kingdom

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  • Jim Stalker,

    Affiliation: Wellcome Trust Sanger Centre, Hinxton, Cambridge, United Kingdom

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  • David Jackson,

    Affiliation: Wellcome Trust Sanger Centre, Hinxton, Cambridge, United Kingdom

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  • Chris Clee,

    Affiliation: Wellcome Trust Sanger Centre, Hinxton, Cambridge, United Kingdom

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  • Robert Plumb,

    Affiliation: Wellcome Trust Sanger Centre, Hinxton, Cambridge, United Kingdom

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  • Jane Rogers,

    Affiliation: Wellcome Trust Sanger Centre, Hinxton, Cambridge, United Kingdom

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  • Sean Humphray,

    Affiliation: Wellcome Trust Sanger Centre, Hinxton, Cambridge, United Kingdom

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  • Tony Cox,

    Affiliation: Wellcome Trust Sanger Centre, Hinxton, Cambridge, United Kingdom

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  • Cordelia Langford,

    Affiliation: Wellcome Trust Sanger Centre, Hinxton, Cambridge, United Kingdom

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  • Adrian Bird mail

    To whom correspondence should be addressed. E-mail: a.bird@ed.ac.uk

    Affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom

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  • Published: January 29, 2008
  • DOI: 10.1371/journal.pbio.0060022

Reader Comments (2)

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The paradox of DNA methylation in transcriptional control

Posted by plosbiology on 07 May 2009 at 22:23 GMT

Author: TIN-LAP LEE
Position: Staff Scientist
Institution: Section on Developmental Genomics, Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health.
E-mail: leetl@mail.nih.gov
Additional Authors: Hoi-Hung Cheung; Andrew Davis; Owen Rennert; Wai-Yee Chan.
Submitted Date: March 19, 2008
Published Date: March 21, 2008
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

DNA methylation is a heritable feature in eukaryotes, its exact role in mammalian development has been controversial. A recent paper published in PLoS biology [1] identified novel CpG islands (CGIs) in different normal tissues and provided intriguing insights on CGI distribution in the genome. Intra- or intergenic CGIs of developmental related genes, such as the HOX family members, were preferentially methylated. It has been proposed CGIs with low or lack of DNA methylation in the promoter regions are usually associated with active gene expression. However, other than CGIs on X chromosome, no direct association between CGI methylation and gene expression was observed and the authors posed an open question about the role of CGI methylation on transcriptional regulation.

In our recent genome-wide analysis (GWA) of global DNA methylation on human germ cell tumor model, we observed the majority of the methylated regions (78%) were in the regions without Refseq annotations, where only less than 9% of methylation is observed in the promoter regions. Subsequent comparison between normal and tumor datasets indicated only 3-4% of DMRs mapped to the promoter regions of known genes. In addition to Illingworth et al’s finding on HOX gene clusters in human normal tissues during development, HOX associated DMRs were frequently present in germ cell tumors and also reported in lung tumors recently [4]. We have so far identified a total of 197 candidate genes with promoter associated DMRs that are highly related to tumor development. Follow-up validation on the promoter associated DMRs by bisulfite sequencing and expression analysis showed no solid correlation between DNA methylation and gene expression. Among 54 DMRs located at the gene promoter region verified (39 hypermethylated DMRs and 15 hypomethylated DMRs), only 35% demonstrated same trend between DNA methylation and gene expression, which is comparable to 37% reported [2]. Again, the Hox gene cluster presented an interesting example in this case. Even though HOXC10 and HOXA7 were among the 39 DMRs with DNA hypermethylation, the expression trend was totally opposite. HOXC10 demonstrated decreased in expression by more than 24 fold in the tumor sample, whereas HOXA7 showed more than 46 fold increase in the same sample. Comparable expression analysis was not done in the lung tumor model study [4]. Given the plasticity of DNA methylation in transcription, the use of methylation markers as an approach to chemotherapy or chemoprevention of cancer has to be with caution.

What are the potential mechanisms that contribute to DNA methylation independent transcription? We hypothesize the involvement of other biological “switches” that override DNA methylation in transcriptional regulation, including acetylation or histone methylation in the promoter region. Another possibility is that DNA methylation changes rapidly within a short period of time [3] and the bisulfite-sequenced DNA was extracted during the wrong snapshot. The wide occurrence of DMRs in the non-coding regions is worth noting. The role of this novel DMR’s class on chromatin structure is still unknown. The unexpected paradigm of DNA methylation in transcription has yet to be fully explored.

1. Illingworth R, Kerr A, Desousa D, Jorgensen H, Ellis P, et al. (2008) A novel CpG island set identifies tissue-specific methylation at developmental gene loci. PLoS Biol 6: e22.

2. Eckhardt F, Lewin J, Cortese R, Rakyan VK, Attwood J, et al. (2006) DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet 38: 1378-1385.

3. Metivier R, Gallais R, Tiffoche C, Le Peron C, Jurkowska RZ, et al. (2008) Cyclical DNA methylation of a transcriptionally active promoter. Nature 452: 45-50.

4. Rauch T, Wang Z, Zhang X, Zhong X, Wu X, et al. (2007) Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay. Proc Natl Acad Sci U S A 104: 5527-5532.

No competing interests declared.