Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification
Lawrence C. Sowers, Shinsuke Ito, Olena Taranova, Kwonho Hong, Ana C. D’Alessio, Yi Zhang
Abstract
DNA methylation is one of the best-characterized epigenetic modifications 1–4. While the enzymes that catalyze DNA methylation have been characterized, enzymes responsible for the reversal process have been elusive 5. A recent study indicates that the human Tet1 protein could catalyze the conversion of 5-methyl-C (5mC) of DNA to 5-hydroxyl-methyl-C (5hmC), raising the possibility that DNA demethylation may be a Tet1-mediated process 6. Here we extended this study by demonstrating that all three mouse Tet proteins can also catalyze a similar reaction. Interestingly, Tet1 plays an important role in mouse ES cell maintenance through maintaining the expression of Nanog in ES cells. Importantly, Tet1 knockdown-mediated down-regulation of Nanog correlated with its promoter methylation, supporting a role for Tet1 in regulating DNA methylation status. Furthermore, knockdown of Tet1 in preimplantation embryos resulted in a bias towards trophectoderm differentiation. Thus, our studies not only uncover the enzymatic activity of the Tet proteins, but also demonstrate a role for Tet1 in ES cell maintenance and ICM cell specification.