Role for Tet in Hyperglycemia-Induced Demethylation: A Novel Mechanism of Diabetic Metabolic Memory

  1. He-Feng Huang
  1. International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; and Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, China
  1. Corresponding author: He-Feng Huang, huanghefg{at}

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. 5-Methylcytosine (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 5-hydroxymethyluracil (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 …

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