Trends in Genetics
ReviewsThe DNA methylation paradox
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.
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