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.

5‐Hydroxymethylcytosine as a clinical biomarker: Fluorescence‐based assay for high‐throughput epigenetic quantification in human tissues

“…5‐Hydroxymethylcytosine (5‐hmC) is an epigenetic modification of the DNA base cytosine, discovered in mammalian genomes in 2009 . 5‐hmC was shown to have a functional role in gene expression regulation, and its global levels were found to be predominantly stable and highly tissue‐specific . A significant global reduction in 5‐hmC level was reported for various human cancers, such as melanoma, colorectal, pancreatic, breast, liver, lung, prostate, brain and blood cancers .…”

Analysis of DNA modifications in aging research

“…With the discovery of the abundance and specific functional roles for alternate cytosine modifications (for reviews, see Moore et al 2013;Shi et al 2017), new methods have emerged in order to distinguish these modifications (hmC, fmC, caC) from mC (Raiber et al 2017). hmC is of the greatest interest given its prevalence and potential regulation with aging (Szulwach et al 2011).…”

Hydroxymethylation Influences on Intestinal Epithelial Cells in Health and Disease

“…At that time hydroxymethylated cytosine was described in a bacteriophage and was suggested to be a mechanism by which the virus evaded DNA degradation by the host [21,22]. Several studies in the 1970s described hydroxymethylated cytosine in mammals but it was not until 2009 when high levels of hydroxymethylation were found in Purkinje cells [23].…”

“…Finally, hydroxymethylation may facilitate passive demethylation as DNTM1 has low ainity for 5-hmc and during DNA replication lack of recognition of a previously methylated cytosine, now 5-hydroxymethylcytosine would not have the methyl mark copied to the daughter strand. Hydroxymethylation not only serves as an intermediate step in active demethylation, but is also fairly stable and present in relative abundance compared to 5-lucytosine and 5-carboxylcytosine; therefore, hydroxymethylation may serve an additional and unique function [21,[26][27][28][29].…”

“…As our sequencing technology and ability to distinguish 5-hmc from 5-mc has improved, we are coming to understand that regions that are rich in 5-hmc may not be "activated" but rather be "poised for activation" through a delicate balance between 5-mc, 5-hmc and activating (H3K4me3) and repressive (H3K27me3) histone marks [21,30]. Furthermore, studies in the central nervous system have indicated that changes in speciic 5-hmc residues without change in overall methylation can have profound efects on gene expression [31].…”