Competitive binding of TET1 and DNMT3A/B cooperates the DNA methylation pattern in human embryonic stem cells

DNMT3A/B and TET1 play indispensable roles in regulating DNA methylation that undergoes extensive reprogramming during mammalian embryogenesis. Yet the competitive and cooperative relationships between TET1 and DNMT3A/B remain largely unknown in the human embryonic stem cells. Here, we revealed that the main DNA-binding domain of TET1 contains more positive charges by using charge reduction of amino acid alphabet, followed by DNMT3A and DNMT3B. The genome-wide binding profiles showed that TET1 prefers binding to the proximal promoters and CpG islands compared with DNMT3A/B. Moreover, the binding regions of these three transcription factors can be divided into specific and co-binding regions. And a stronger inhibitory effect of DNMT3A on TET1 demethylation was observed in co-binding regions. Furthermore, we integrated TET1 knockout data to further discuss the competitive binding patterns of TET1 and DNMT3A/B. The lack of TET1 increased the occupation of DNMT3A/B at the specific binding regions of TET1 causing focal hypermethylation. The knockout of TET1 was also accompanied by a reduction of DNMT3A/B binding in the co-binding regions, further confirming the cooperative binding function between TET1 and DNMT3A/B. In conclusion, our studies found that the competitive binding of TET1 and DNMT3A/B cooperatively shapes the global DNA methylation pattern in human embryonic stem cells.