DNA methylation & cancer garvan institute

DNA & cell types

All human cells contain the same DNA sequence. Differences in structure and function come from cells expressing only certain genes. Epigenetic modifications (chemical tags) regulate gene expression.

DNA methylation

A key epigenetic modification. Methyl groups added to DNA, usually at promoter regions, are associated with gene silencing. Important for maintaining stable cell types. In cancer, methylation patterns are disrupted.

DNA methyltransferases (DNMTs)

Enzyme family responsible for DNA methylation. Three major types: DNMT1, DNMT3A, DNMT3B. Each has distinct roles in development and cell division.

DNMT3A & DNMT3B (de novo methylation)

Active after fertilization in early embryonic cells. Establish new methylation patterns, allowing embryonic cells to differentiate into specific cell types (e.g., skin cell).

DNMT1 (maintenance methylation)

Preserves existing methylation patterns during cell division. Ensures daughter cells inherit the same gene expression program as parent cells.

Methylation patterns & cell identity

Each cell type has a unique methylation pattern → reflects its specific gene expression program (e.g., skin cells maintain skin-specific genes).

CpG sites & CpG islands

CpG = cytosine followed by guanine in DNA. Found throughout genome. CpG islands = clusters of CpGs, often in promoter regions. In normal adult cells: most CpGs are methylated, but promoter CpG islands are usually unmethylated → allows gene transcription.

Methylation chemistry

DNMT3A/3B obtain methyl groups from SAM (S-adenosyl methionine). Mechanism: cytosine base is flipped 180° out of DNA strand → DNMT transfers methyl group → forms 5-methylcytosine → base flips back into strand.

TET enzymes & demethylation

TET (Ten-Eleven Translocation) enzymes regulate DNA demethylation. They oxidize 5-methylcytosine to 5-hydroxymethylcytosine. Through further pathways, this is converted back to cytosine. TET = active DNA demethylation process.

Balance of methylation vs demethylation

In normal cells, DNMT (methylation) and TET (demethylation) are tightly regulated, ensuring correct gene expression during development.

Cancer & DNA methylation changes

Regulation is disrupted in cancer.

Hypermethylation of promoter CpG islands → silences tumor suppressor genes.

Global hypomethylation across genome → genomic instability.
Together = “bimodal deregulation” of epigenetic landscape.

Universal cancer feature

Every type of human tumor shows this pattern: focal promoter hypermethylation + widespread hypomethylation.

Clinical application

Altered DNA methylation patterns can be used to distinguish cancer cells from normal cells → biomarker for cancer detection.