New Insights into 5hmC DNA Modification: Generation, Distribution and Function

Abstract

Dynamic DNA modifications, such as methylation/demethylation on cytosine, are major epigenetic mechanisms to modulate gene expression in both eukaryotes and prokaryotes. In addition to the common methylation on the 5th position of the pyrimidine ring of cytosine (5mC), other types of modifications at the same position, such as 5-hydroxymethyl (5hmC), 5-formyl (5fC), and 5-carboxyl (5caC), are also important. Recently, 5hmC, a product of 5mC demethylation by the Ten-Eleven Translocation family proteins, was shown to regulate many cellular and developmental processes, including the pluripotency of embryonic stem cells, neuron development, and tumorigenesis in mammals. Here, we review recent advances on the generation, distribution, and function of 5hmC modification in mammals and discuss its potential roles in plants.

Keywords: 5-hydroxymethylcytosine; DNA demethylation; DNA hydroxylation; TET proteins; epigenetics.

FIGURE 1

Different types of DNA modification.

FIGURE 2

DNA demethylation in mammals. DNA demethylation is executed through passive demethylation (light blue chart) and active demethylation (gray chart). DNA methylation is maintained by DNA methyltransferases (DNMTs) during replication. 5mC will be replaced by C if methylation maintenance fails in passive demethylation. Active demethylation is achieved by Ten-Eleven Translocation (TET) proteins which can stepwise oxidize 5mC to 5hmC, 5fC and 5caC. Subsequently an abasic site is generated and filled in with an unmodified C by thymine-DNA glycosylase (TDG) and base-excision repair (BER) pathway. Furthermore, Lin28A is reported to recruit TET1 and NEIL proteins involved in excision of 5hmC, 5fC, and 5caC.