CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future.
TLDR
Basic and translational studies will both be needed in the near future to fully understand the mechanisms, roles and uses of CpG island hypermethylation in human cancer.Abstract:
We have come a long way since the first reports of the existence of aberrant DNA methylation in human cancer. Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is now firmly established as an important mechanism for gene inactivation. CpG island hypermethylation has been described in almost every tumor type. Many cellular pathways are inactivated by this type of epigenetic lesion: DNA repair (hMLH1, MGMT), cell cycle (p16INK4a, p15INK4b, p14ARF), apoptosis (DAPK), cell adherence (CDH1, CDH13), detoxification (GSTP1), etc … However, we still know little of the mechanisms of aberrant methylation and why certain genes are selected over others. Hypermethylation is not an isolated layer of epigenetic control, but is linked to the other pieces of the puzzle such as methyl-binding proteins, DNA methyltransferases and histone deacetylase, but our understanding of the degree of specificity of these epigenetic layers in the silencing of specific tumor suppressor genes remains incomplete. The explosion of user-friendly technologies has given rise to a rapidly increasing list of hypermethylated genes. Careful functional and genetic studies are necessary to determine which hypermethylation events are truly relevant for human tumorigenesis. The development of CpG island hypermethylation profiles for every form of human tumors has yielded valuable pilot clinical data in monitoring and treating cancer patients based in our knowledge of DNA methylation. Basic and translational will both be needed in the near future to fully understand the mechanisms, roles and uses of CpG island hypermethylation in human cancer. The expectations are high.read more
Citations
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Patent
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Book ChapterDOI
Epigenetic regulation of mammalian imprinted genes: from primary to functional imprints.
TL;DR: This chapter presents a general overview of the field and describes in detail the 'imprinting cycle', and provides selected examples that recapitulate the current knowledge of epigenetic regulation at imprinted loci.
References
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Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands
TL;DR: The use of MSP is demonstrated to identify promoter region hypermethylation changes associated with transcriptional inactivation in four important tumor suppressor genes (p16, p15, E-cadherin and von Hippel-Lindau) in human cancer.
Journal ArticleDOI
CpG-rich islands and the function of DNA methylation
TL;DR: It is likely that most vertebrate genes are associated with ‘HTF islands’—DNA sequences in which CpG is abundant and non-methylated; however, highly tissue-specific genes, though, usually lack islands.
Journal ArticleDOI
Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex
Xinsheng Nan,Huck-Hui Ng,Colin A. Johnson,Carol D. Laherty,Bryan M. Turner,Robert N. Eisenman,Adrian Bird +6 more
TL;DR: The data suggest that two global mechanisms of gene regulation, DNA methylation and histone deacetylation, can be linked by MeCP2, an abundant nuclear protein that is essential for mouse embryogenesis.
Journal ArticleDOI
Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.
Peter L. Jones,Gert C. Jan Veenstra,Paul A. Wade,Danielle Vermaak,Stefan U. Kass,Nicoletta Landsberger,John Strouboulis,Alan P. Wolffe +7 more
TL;DR: The results establish a direct causal relationship between DNA methylation-dependent transcriptional silencing and the modification of chromatin.
Journal ArticleDOI
Cancer-epigenetics comes of age
Peter A. Jones,Peter W. Laird +1 more
TL;DR: Current mechanistic understanding of the role of DNA methylation in malignant transformation is reviewed, and it is suggested Knudson's two–hit hypothesis should be expanded to include epigenetic mechanisms of gene inactivation.