A primary role of TET proteins in establishment and maintenance of De Novo bivalency at CpG islands

Nucleic Acids Res. 2016 Oct 14;44(18):8682-8692. doi: 10.1093/nar/gkw529. Epub 2016 Jun 10.


Ten Eleven Translocation (TET) protein-catalyzed 5mC oxidation not only creates novel DNA modifications, such as 5hmC, but also initiates active or passive DNA demethylation. TETs' role in the crosstalk with specific histone modifications, however, is largely elusive. Here, we show that TET2-mediated DNA demethylation plays a primary role in the de novo establishment and maintenance of H3K4me3/H3K27me3 bivalent domains underlying methylated DNA CpG islands (CGIs). Overexpression of wild type (WT), but not catalytic inactive mutant (Mut), TET2 in low-TET-expressing cells results in an increase in the level of 5hmC with accompanying DNA demethylation at a subset of CGIs. Most importantly, this alteration is sufficient in making de novo bivalent domains at these loci. Genome-wide analysis reveals that these de novo synthesized bivalent domains are largely associated with a subset of essential developmental gene promoters, which are located within CGIs and are previously silenced due to DNA methylation. On the other hand, deletion of Tet1 and Tet2 in mouse embryonic stem (ES) cells results in an apparent loss of H3K27me3 at bivalent domains, which are associated with a particular set of key developmental gene promoters. Collectively, this study demonstrates the critical role of TET proteins in regulating the crosstalk between two key epigenetic mechanisms, DNA methylation and histone methylation (H3K4me3 and H3K27me3), particularly at CGIs associated with developmental genes.

MeSH terms

  • Animals
  • CpG Islands / genetics*
  • DNA Methylation / genetics
  • DNA-Binding Proteins / metabolism*
  • Dioxygenases
  • Embryonic Stem Cells / metabolism
  • Genome
  • HEK293 Cells
  • Histones / metabolism
  • Humans
  • Lysine / metabolism
  • Mice
  • Models, Biological
  • Proto-Oncogene Proteins / metabolism*
  • Transcription, Genetic


  • DNA-Binding Proteins
  • Histones
  • Proto-Oncogene Proteins
  • TET1 protein, mouse
  • Dioxygenases
  • TET2 protein, human
  • Tet2 protein, mouse
  • Lysine