CpG Island Methylation and Silencing

CpG islands are CG-rich stretches of DNA found at the promoters of many genes; in normal cells they are usually kept unmethylated, allowing transcription. When such an island becomes densely methylated, the associated gene is typically silenced. This topic explains how aberrant CpG-island methylation switches genes off — a mechanism central to the silencing of tumour-suppressor genes in cancer.

Definition

A CpG island is a region of DNA with a high frequency of CpG dinucleotides, often located at gene promoters; CpG-island methylation refers to the addition of methyl groups to the cytosines in such an island, which, when dense at a promoter, is generally associated with stable transcriptional silencing of the corresponding gene.

Scope

The entry covers what CpG islands are, the normal unmethylated state of promoter islands, the link between dense island methylation and transcriptional silencing, and the role of promoter hypermethylation in inactivating tumour-suppressor genes. It is a mechanistic reference and not clinical guidance.

Core questions

• Why are most promoter CpG islands normally unmethylated?
• How does dense island methylation lead to gene silencing?
• How does promoter hypermethylation inactivate tumour-suppressor genes?
• Why can hypermethylation substitute for a coding mutation in cancer?

Key concepts

• CpG dinucleotide
• Promoter CpG island
• Unmethylated active state
• Promoter hypermethylation
• Transcriptional silencing
• Tumour-suppressor inactivation
• Two-hit inactivation

Mechanisms

CpG islands at gene promoters are normally protected from methylation, keeping the local chromatin open and the gene transcribable. When DNA methyltransferases methylate the cytosines across such an island, the methylated DNA recruits methyl-binding proteins and repressive chromatin, the promoter is packaged into a closed configuration, and transcription is shut down. In cancer this aberrant hypermethylation silences tumour-suppressor genes, providing an alternative to a deleting or inactivating mutation; combined with loss of the other allele, promoter hypermethylation can complete the two-hit inactivation of a tumour-suppressor gene.

Clinical relevance

Promoter hypermethylation of specific genes is studied as a tissue and circulating biomarker for cancer detection and classification. This entry describes the underlying mechanism for educational purposes and does not constitute diagnostic or treatment advice.

Epidemiology

Aberrant promoter CpG-island hypermethylation of tumour-suppressor genes is observed across a wide range of human cancers; the particular genes silenced and the frequency of their methylation differ by tumour type and are detailed in disease-specific literature.

History

After global hypomethylation was found in tumours, researchers identified the paradoxical local hypermethylation of promoter CpG islands and linked it to gene silencing. Herman and Baylin's 2003 review consolidated promoter hypermethylation as a mechanism of gene silencing in cancer, and subsequent epigenome mapping placed it within the broader landscape of DNA-methylation alterations described by Jones, Baylin, and Esteller.

Debates

Is promoter hypermethylation a cause or a marker of silencing?

Whether dense island methylation initiates silencing or instead locks in a silent state established by other chromatin changes has been debated, with evidence that methylation both follows and reinforces repressive chromatin at vulnerable promoters.

Key figures

• Stephen Baylin
• James Herman
• Peter A. Jones
• Adrian Bird

Seminal works

• jones-baylin-2002
• herman-baylin-2003
• esteller-2007

Frequently asked questions

Does CpG-island methylation always silence a gene?

Dense methylation of a promoter CpG island is generally associated with silencing, but not every CpG site or every island behaves the same way; the strong silencing link is mainly for dense methylation of promoter-associated islands.

How can methylation inactivate a gene without mutating it?

Methylation recruits repressive chromatin that closes the promoter and blocks transcription, so the gene's product is lost even though its coding sequence is intact.