DNA Methylation and DNA Hydroxymethylation

DNA methylation patterns throughout the genome are established and maintained by the DNA methyltransferases (DNMTs), known as DNMT1, DNMT3A and DNMT3B. DNMT3L is an inactive cofactor that works with DNMT3A and DNMT3B to modulate their activity and targeting. Methyl groups on cytosine can be oxidized iteratively to 5-hydroxymethyl, 5-formyl and 5-carboxyl moieties by the ten-eleven translocation (TET) family of proteins — TET1, TET2 and TET3 — yielding four possible DNA epigenetic marks at cytosine, typically within the 5'—C—phosphate—G—3' (CpG) context. Evidence also shows that the TETs collaborate with DNA repair factors such as thymine DNA glycosylase (TDG), to restore modified cytosine back to its ground, unmodified state.

Using in vitro cell culture models and human tissue, the Epigenetic Etiology of Human Disease Laboratory is defining how the DNMTs and TETs regulate the targeting, activity and deposition of cytosine modifications under normal and disease conditions. Genome-wide mapping studies have linked the DNMTs to DNA methylation within actively transcribed gene bodies and revealed unique and overlapping targets of each DNMT. Studies of the division of labor among the TET proteins, and how mutations in TET family members such as TET2 contribute to tumor initiation and progression, are underway.

DNA methylation and hydroxymethylation are key regulators of cell growth control and differentiation. Mutations in TET proteins occur in many human tumors (for example, TET2 in myeloid malignancies); yet there is a lack of understanding of how these pathways drive deregulated cell growth. Work in this area is expected to yield novel information on how aberrant epigenetic changes occur, why these changes lead to cancer, and how they can be targeted with drugs or prevented through chemoprevention and lifestyle change.