Recent Advances in Deciphering the Mechanisms and Biological Functions of DNA Demethylation

Abstract

Comprehensive Summary5‐Methylcytosine (5mC) is a dynamic and reversible epigenetic modification in genomic DNA of higher eukaryotes. It has been well‐established that the demethylation of 5mC occurs through the ten‐eleven translocation (TET)‐mediated oxidation of 5mC followed by thymine DNA glycosylase (TDG)‐initiated base excision repair (BER). Recent findings also have identified an alternative pathway of DNA demethylation. In this pathway, TET enzymes directly oxidize 5mC to form 5‐formylcytosine (5fC) or 5‐carboxylcytosine (5caC) through C–C bond cleavage. These modified bases can undergo direct deformylation or decarboxylation, respectively. Additionally, DNA demethylation can also occur through the deamination of 5mC and 5hmC, resulting in the production of thymine and 5‐hydroxymethyluracil (5hmU), respectively. Various DNA demethylation pathways possess critical functional implications and roles in biological processes. This Recent Advances article will focus on the studies of mechanisms and biological functions of DNA demethylation, shedding light on the reversible nature of the epigenetic modification of 5mC.This article is protected by copyright. All rights reserved.

Whole-Genome Mapping of Epigenetic Modification of 5-Formylcytosine at Single-Base Resolution by Chemical Labeling Enrichment and Deamination Sequencing

“…The 10-11 translocation (TET) dioxygenases can sequentially oxidize 5mC to generate three modified forms of cytosine, 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). − Thymine DNA glycosylase (TDG) plays a role in recognizing and removing 5fC and 5caC from the genomic DNA, which triggers a repair process known as base excision repair and leads to the restoration of unmodified cytosine. − Although 5fC was initially discovered in mouse embryonic stem cells (mESCs), its abundance is lower compared to 5hmC and 5mC. , Aside from its role as an intermediate in DNA demethylation, 5fC has been found to influence the structure of the DNA double helix . It has also been suggested that 5fC and its oxidative counterpart, 5caC, can potentially serve as targets for specific reader proteins, implying that they may have regulatory functions in gene expression and chromatin organization. , …”

Simultaneous detection of 5-methylcytosine and 5-hydroxymethylcytosine at specific genomic loci by engineered deaminase-assisted sequencing

“…6–9 5fC and 5caC can be converted back to unmodified cytosines through the base excision repair pathway or through direct deformylation or decarboxylation. 10–13 Despite being the two most prevalent DNA modifications, the biological functions of 5mC and 5hmC in DNA often have opposing effects, and abnormal DNA methylation or hydroxymethylation is closely linked to various diseases. 14–17…”