Background: DNA methylation is a heritable epigenetic mark, enabling stable but reversible gene repression. In mammalian cells, DNA methyltransferases (DNMTs) are responsible for modifying cytosine to 5-methylcytosine (5mC), which can be further oxidized by the TET dioxygenases to ultimately cause DNA demethylation. However, the genome-wide cooperation and functions of these two families of proteins, especially at large under-methylated regions, called canyons, remain largely unknown. Results: Here we demonstrate that DNMT3A and TET1 function in a complementary and competitive manner in mouse embryonic stem cells to mediate proper epigenetic landscapes and gene expression. The longer isoform of DNMT3A, DNMT3A1, exhibits significant enrichment at distal promoters and canyon edges, but is excluded from proximal promoters and canyons where TET1 shows prominent binding. Deletion of Tet1 increases DNMT3A1 binding capacity at and around genes with wild-type TET1 binding. However, deletion of Dnmt3a has a minor effect on TET1 binding on chromatin, indicating that TET1 may limit DNA methylation partially by protecting its targets from DNMT3A and establishing boundaries for DNA methylation. Local CpG density may determine their complementary binding patterns and therefore that the methylation landscape is encoded in the DNA sequence. Furthermore, DNMT3A and TET1 impact histone modifications which in turn regulate gene expression. In particular, they regulate Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3 enrichment to constrain gene expression from bivalent promoters. Conclusions: We conclude that DNMT3A and TET1 regulate the epigenome and gene expression at specific targets via their functional interplay.
Bibliographical noteFunding Information:
This work was supported by NIH grants: HG007538 and CA193466 (to WL); AI121403 and 1R01AI121403-01A1 (to TC); and DK092883 and CA183252 (to MAG); as well as CPRIT grants: RR140053 (to YH); and CP120348 and CP170002 (to JS). This work was also supported by the American Heart Association (16IRG27250155 to YH) and Texas A&M University start-up funds (to YH and DS). MJ was supported by 5T32DK60445.
- DNA methylation
- Embryonic stem cells