DNA Methyltransferases and TET Enzymes

DNA methyltransferases (DNMTs) write the methyl mark onto cytosine, while TET (ten-eleven translocation) enzymes initiate its removal by oxidising 5-methylcytosine. Together they form the writer-and-eraser machinery of DNA methylation: DNMT3 enzymes establish new patterns de novo, DNMT1 maintains them through replication, and TET enzymes provide an active route to demethylation.

Definition

DNA methyltransferases are enzymes that transfer a methyl group onto cytosine to establish or maintain DNA methylation, while TET enzymes are dioxygenases that oxidise 5-methylcytosine to 5-hydroxymethylcytosine and further products, initiating active DNA demethylation.

Scope

The entry covers the DNMT family (de novo versus maintenance roles) and the TET family (oxidation of 5-methylcytosine toward demethylation), and how their opposing activities set and reset DNA methylation patterns. It is reference-educational and does not provide therapeutic dosing or individualised advice.

Core questions

• How do de novo and maintenance methyltransferases differ in function?
• How is a methylation pattern copied after DNA replication?
• How do TET enzymes initiate the removal of cytosine methylation?
• What is 5-hydroxymethylcytosine and why does it matter?

Key concepts

• DNMT1 (maintenance methyltransferase)
• DNMT3A and DNMT3B (de novo methyltransferases)
• Hemimethylated DNA recognition
• TET1/TET2/TET3 dioxygenases
• 5-hydroxymethylcytosine
• Active versus passive demethylation

Mechanisms

DNMT3A and DNMT3B establish new (de novo) methylation patterns during development, transferring methyl groups from S-adenosylmethionine onto previously unmethylated cytosines; loss of these enzymes is incompatible with normal mammalian development. DNMT1 acts as the maintenance enzyme, preferentially recognising hemimethylated CpG sites generated by replication and restoring symmetric methylation, thereby copying patterns to daughter cells. TET enzymes (TET1, TET2, TET3) oxidise 5-methylcytosine to 5-hydroxymethylcytosine and onward to further oxidised bases; these can be removed and replaced with unmodified cytosine through base-excision repair, providing an active demethylation pathway, while failure to maintain methylation during replication causes passive demethylation. The opposing writer and eraser activities together make DNA methylation a dynamic, resettable mark.

Clinical relevance

DNMT and TET genes are recurrently altered in haematological and other malignancies and are studied as research drug targets, and their activity shapes the methylomes interpreted in epigenomic studies. This entry describes their molecular roles as reference material and is not a basis for individual diagnosis or treatment.

Evidence & guidelines

The de novo and maintenance division of DNMT labour was established by Okano and colleagues, and the demethylation function of TET enzymes was opened by Tahiliani and colleagues' identification of 5-hydroxymethylcytosine production and corroborated by Ito and colleagues. Reviews by Bird and by Smith and Meissner integrate these enzymes into the broader methylation cycle; mechanistic details of TET-driven demethylation in specific contexts continue to be refined.

History

The maintenance-methyltransferase concept long predated molecular identification of the enzymes; cloning of DNMT1 and then the DNMT3 de novo enzymes in the 1990s defined the writing machinery. The long-standing puzzle of how methylation is actively erased was resolved beginning in 2009, when TET1 was shown to oxidise 5-methylcytosine to 5-hydroxymethylcytosine, revealing an enzymatic demethylation route and a new modified base in the genome.

Key figures

• En Li
• Masaki Okano
• Anjana Rao
• Mamta Tahiliani
• Yi Zhang

Seminal works

• okano-1999
• tahiliani-2009
• ito-2010

Frequently asked questions

What is the difference between de novo and maintenance methyltransferases?

De novo enzymes (DNMT3A and DNMT3B) add methylation to previously unmethylated cytosines to establish new patterns, while the maintenance enzyme (DNMT1) copies existing methylation onto the new strand after DNA replication.

How do TET enzymes remove DNA methylation?

TET enzymes oxidise 5-methylcytosine to 5-hydroxymethylcytosine and further oxidised forms; these can be repaired back to unmodified cytosine, providing an active demethylation pathway, or methylation can be lost passively if not maintained during replication.