DNA Methylation

DNA methylation is the covalent addition of a methyl group to a DNA base, most commonly to the carbon-5 position of cytosine to form 5-methylcytosine. In mammals it occurs predominantly at CpG dinucleotides and is a central, heritable mechanism for regulating gene expression, marking transposable elements, and maintaining stable cell-type identity.

Definition

DNA methylation is the enzymatic transfer of a methyl group to cytosine (forming 5-methylcytosine), predominantly within CpG dinucleotides in mammals, producing a heritable mark that modulates transcription and chromatin state without changing the DNA sequence.

Scope

The entry covers where methylation occurs in the genome (CpG sites and CpG islands), how it influences transcription, how patterns are maintained through cell division, and how genome-wide methylation is measured. It treats DNA methylation as a molecular epigenetics topic and is reference-educational, not clinical guidance.

Core questions

• Where in the genome does cytosine methylation occur and what distinguishes CpG islands?
• How does methylation at a promoter relate to transcriptional silencing?
• How is the methylation pattern copied to daughter cells after DNA replication?
• How is genome-wide methylation measured at single-base resolution?

Key concepts

• 5-methylcytosine
• CpG dinucleotide
• CpG island
• Promoter hypermethylation and silencing
• Hemimethylated DNA and maintenance
• Methylome
• Whole-genome bisulfite sequencing

Key theories

Epigenetic memory via maintenance methylation

Symmetric CpG methylation is copied after replication by a maintenance methyltransferase acting on hemimethylated DNA, providing a molecular basis for heritable transmission of gene-expression states across cell generations.

Mechanisms

A methyl group is added to cytosine within CpG dinucleotides, generating 5-methylcytosine. CpG islands, which are CpG-dense regions overlapping many promoters, are typically unmethylated in active genes; methylation of a promoter-associated island is associated with stable transcriptional silencing, in part by impeding transcription-factor binding and by recruiting methyl-CpG-binding proteins and repressive chromatin complexes. Because CpG is a palindrome, methylation is symmetric on the two strands; after replication the daughter duplex is hemimethylated, and a maintenance methyltransferase restores full methylation, copying the pattern to both daughter cells. Genome-wide, methylation also silences transposable elements and contributes to genomic imprinting and X-chromosome inactivation.

Clinical relevance

Altered DNA methylation patterns are described in cancer and other conditions, and methylation profiling is widely used in epigenomic research and biomarker studies. This entry explains the mechanism as background for interpreting such studies; it is descriptive and not a basis for individual diagnostic or treatment decisions.

Evidence & guidelines

Base-resolution methylome maps such as Lister and colleagues' human methylome established that methylation is dynamic and tissue-specific, while reviews by Bird and by Smith and Meissner consolidated its developmental and regulatory roles. The association between promoter-island methylation and silencing is well supported, though the directionality and function of methylation in gene bodies and at other sites remain areas of active refinement.

History

Methylation of cytosine was recognised as a candidate carrier of heritable regulatory information in the late 1970s and 1980s, with models proposing that symmetric CpG methylation could be maintained through replication. Bird's work clarified the link between methylation, CpG islands, and stable gene control, and the advent of bisulfite sequencing and then whole-genome single-base mapping turned methylation into a genome-wide readable layer of epigenetic information.

Debates

Is promoter methylation a cause or a consequence of silencing?

Promoter-island methylation is tightly associated with transcriptional silencing, but whether it initiates silencing or locks in a state established by other repressive events is context-dependent and debated.

Key figures

• Adrian Bird
• Aimee Deaton
• Alexander Meissner
• Ryan Lister
• Joseph Ecker

Seminal works

• bird-2002
• deaton-bird-2011
• lister-2009

Frequently asked questions

What is a CpG island?

A CpG island is a region of DNA with an unusually high density of CpG dinucleotides, often overlapping gene promoters. These islands are typically unmethylated when their associated gene is active.

How is a methylation pattern inherited by daughter cells?

Because CpG methylation is symmetric on both strands, replication produces hemimethylated DNA; a maintenance methyltransferase then methylates the new strand, copying the pattern faithfully to each daughter cell.