Trends in Genetics
Volume 15, Issue 1, 1 January 1999, Pages 34-37
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The DNA methylation paradox

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Abstract

The methylation of CpG islands is often equated with transcriptional inactivity and there is overwhelming evidence that this is the case for islands located in gene promoters. Such methylation is probably part of a mechanism to permanently silence the activities of genes, including those on the inactive X chromosome. Not all CpG islands and methylation sites are located in known promoters; several tissue-specific and imprinted genes have CpG islands located at considerable distances downstream of transcription initiation sites, and many genes have multiple promoters. Methylation of CpG islands downstream of transcription initiation does not block elongation in mammalian cells. This has given rise to an interesting paradox in which methylation in the transcribed region is often correlated with expression, in contrast to the inverse correlation seen at the site of transcriptional initiation. The methylation paradox might be resolved if it is hypothesized that transcription through a CpG island facilitates de novo methylation.

Section snippets

DNA methylation suppresses rather than ‘regulates’ gene expression

It is now almost 25 years since Riggs4 and Holliday and Pugh5 proposed that DNA methylation was part of a system for controlling gene expression in mammalian cells. ‘Control’ implies reversibility, yet subsequent work has shown that the most likely function of DNA methylation is permanent gene suppression mediated through the modification of CpG islands located in the promoter regions of genes. Box 1 lists data convincingly demonstrating that methylation of CpG-rich promoters can be extensive,

CpG island methylation does not prevent transcriptional elongation in mammals

The mechanism by which methylation suppresses promoter activities is becoming clearer with the cloning and identification of methylated-DNA-binding proteins, which bind to methylated CpG islands, presumably excluding the access required by transcription factors for the initiation of transcription. Methylated-DNA-binding proteins also recruit histone deacetylase activity, suggesting that the binding proteins could induce a suppressed chromatin configuration at the transcription initiation site,

Does transcription facilitate de novo methylation?

The methylation paradox might be resolved if it is postulated that the movement of the transcriptional complex through a CpG island can target it for de novo methylation. In many cases, the degree of methylation observed in the CpG island is correlated with an increased rather than a decreased level of expression in some of the genes listed in Table 2. A good example is the mouse insulin-like growth factor 2 receptor gene (Igf2r), where transcription of the sense strand on the maternal gene

How does DNA methylation contribute to tumor progression?

Alterations in the patterns of DNA methylation are one of the most common genomic alterations seen in human cancer23, 24. Abnormal methylation of CpG islands in the promoters of well-characterized tumor suppressor genes, such as those encoding retinoblastoma, Von-Hippel Lindau, and p16, can contribute to their functional inactivation, thus fulfilling one of the hits to satisfy Knudson's hypothesis. Additionally, other genes relevant to cancer development such as DNA-repair genes (e.g. MLH1) are

Summary

Methylation of DNA is essential for mammalian development27 and probably participates as part of a gene- silencing mechanism in eukaryotic cells. The mechanism might have evolved originally to allow for the suppression of the promoters of parasitic DNA sequences that invaded the vertebrate genome15. An essential component of this hypothesis is that the methylation of CpG islands situated within the transcriptional units of genes should not block the transcription of the gene but, rather, should

Acknowledgements

Supported by grant R35 CA49758 from the National Cancer Institute. I thank G. Liang and C. Windham for their help with the figures.

References (33)

  • X. Nan

    Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex

    Nature

    (1998)
  • P.L. Jones

    Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription

    Nat. Genet.

    (1998)
  • K.D. Robertson

    Transcriptional activation of the Epstein–Barr virus latency C promoter after 5-azacytidine treatment: evidence that demethylation at a single CpG site is crucial

    Mol. Cell. Biol.

    (1995)
  • C.L. Hsieh

    Dependence of transcriptional repression on CpG methylation density

    Mol. Cell. Biol.

    (1994)
  • C.L. Hsieh

    Stability of patch methylation and its impact in regions of transcriptional initiation and elongation

    Mol. Cell. Biol.

    (1997)
  • S.U. Kass

    Inactive chromatin spreads from a focus of methylation

    Mol. Cell. Biol.

    (1993)
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