Role for tet in hyperglycemia-induced demethylation: a novel mechanism of diabetic metabolic memory.

During germ cell and early embryonic development— the most sensitive and vulnerable period of epigenetic reprogramming—exposure to an adverse environment leads to abnormal methylation and, possibly, long-term health problems. DNA methylation, a major epigenetic mechanism for gene silencing, is recognized to be responsible for the stability of gene expression status. The majority of cytosine-phosphate-guanine sites (CpGs) in mammalian genomes are methylated. DNA methyltransferase (Dnmt) 3A and 3B are essential for de novo methylation, and Dnmt1 maintains methylation patterns during cell division (1). Establishment and maintenance of cell type–specific DNA methylation patterns are dependent on both methylation and demethylation. DNA demethylation is the process of the removal of a methyl group from nucleotides in DNA, which can be passive or active. It has been generally understood that passive DNA demethylation occurs by a reduction in activity or absence of Dnmts, whereas the mechanism of active DNA demethylation has been controversial in recent decades. Recently, three enzyme families have been implicated in active DNA demethylation via DNA repair. The first is the ten-eleven translocation (Tet) family of enzymes. 5Methylcytosine (5mC) can be hydroxylated by Tet to form 5-hydroxymethylcytosine (5hmC), which can be further oxidized to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). The second family is the AID/APOBEC family. 5mC (or 5hmC) can be deaminated by AID/APOBEC family members to form 5-methyluracil (5mU) or 5hydroxymethyluracil (5hmU). The third is the UDG family of base excision repair glycosylases. TDG and SMUG1 replace these intermediates (i.e., 5mU, 5hmU, or 5caC), culminating in cytosine replacement and DNA demethylation (2–4). Environment and nutrition have been confirmed to affect epigenetic modification. Although it has been documented that hyperglycemia induces demethylation of specific cytosines throughout the genome (5,6), whether the demethylation could be persistent, and the mechanism involved need to be further investigated. In this issue, Dhliwayo et al. (7) used a zebrafish model to elucidate the potential molecular mechanism that is responsible for hyperglycemia-induced DNA demethylation. This is a very interesting study when considered in the context of previous findings from this team. In previous studies, these investigators found that the zebrafish demonstrates metabolic memory (MM). Hyperglycemia was induced by streptozocin in adult zebrafish, and following streptozocin withdrawal, they were allowed to reestablish euglycemia. Blood glucose and serum insulin returned to physiological levels because of pancreatic b-cell regeneration, whereas caudal fin regeneration and skin wound healing remained impaired to the same extent as observed in diabetic zebrafish, and this impairment was transmitted to daughter cell tissue. Furthermore, the investigators found that hyperglycemia caused genome-wide demethylation and aberrant gene expression that were inherited by daughter cells and may contribute to the MM (8). They hypothesized that this may be an explanation for heritable transmission of diabetic MM induced by instant exposure in hyperglycemia. In the new study by Dhliwayo et al. (7), the most notable result concerns a role for the Tet in hyperglycemiainduced DNA demethylation. They provided evidence that hyperglycemia induces both expression and activity of the Tet enzymes, yielding known intermediates of the iterative oxidation pathway that leads to demethylation of 5mC. As 5hmC is the common intermediate for the Tet-specific demethylation, they examined 5hmC