Mechanisms regulating DNA methylation and DNA hydroxymethylation

  • The interaction of DNA methylation and DNA hydroxymethylation
  • Schematic structure of the mammalian (A) DNA methyltransferase (DNMT) family and (B) ten-eleven-translocation (TET) family are shown.

  • ChIP-sequencing for DNMT1, DNMT3A and DNMT3B binding across the genome of a pluripotent human cancer cell line stratified by gene expression levels. This reveals increased DNMT binding as a function of expression level (stratified into high, medium and low). This is consistent with the enrichment of DNA methylation in more-actively transcribed gene bodies.

DNA methylation patterns throughout the genome are established and maintained by the DNA methyltransferases (DNMTs), known as DNMT1, DNMT3A and DNMT3B. Recently, methyl groups on DNA were discovered that could be oxidized to 5-hydroxymethyl groups by the ten-eleven-translocation (TET) family of proteins, TET1, TET2 and TET3, establishing a new DNA epigenetic mark. Evidence also shows that the TETs further act on 5-hydroxymethyl groups in collaboration with DNA repair factors, establishing an unmodified, unmethylated state.

Using in vitro, cell culture and animal models, the laboratory is defining how the DNMTs and TETs work with methylated and hydroxymethylated human DNA under normal and disease conditions. Whole-genome mapping studies (ChIP-sequencing) have linked 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 contribute to tumor initiation and promotion are underway.

DNA methylation and hydroxymethylation are key regulators of cell growth control and differentiation. Mutations in TET proteins occur in some human tumors (for example, myeloid malignancies), yet there is a lack of understanding of how these pathways are regulated. This work 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 or lifestyle change.