5‐hydroxymethylcytosine marks postmitotic neural cells in the adult and developing vertebrate central nervous system

Abstract

The epigenetic mark 5-hydroxymethylcytosine (5hmC) is a cytosine modification that is abundant in the central nervous system of mammals and which results from 5-methylcytosine oxidation by TET enzymes. Such a mark is suggested to play key roles in the regulation of chromatin structure and gene expression. However, its precise functions still remain poorly understood and information about its distribution in non-mammalian species is still lacking. Here, the distribution of 5hmC was investigated in the brain of adult zebrafish, African claw frog, and mouse in a comparative manner. We show that zebrafish neurons are endowed with high levels of 5hmC, whereas quiescent or proliferative neural progenitors show low to undetectable levels of the modified cytosine. In the brain of larval and juvenile Xenopus, 5hmC is also detected in neurons, while ventricular proliferative cells do not display this epigenetic mark. Similarly, 5hmC is enriched in neurons compared to neural progenitors of the ventricular zone in the mouse developing cortex. Interestingly, 5hmC colocalized with the methylated DNA binding protein MeCP2 and with the active chromatin histone modification H3K4me2 in mouse neurons. Taken together, our results show an evolutionarily conserved cerebral distribution of 5hmC between fish and tetrapods and reinforce the idea that 5hmC fulfills major functions in the control of chromatin activity in vertebrate neurons. J. Comp. Neurol. 525:478-497, 2017. © 2016 Wiley Periodicals, Inc.

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

“…As a reader for both 5mC and 5hmC (Mellén et al, 2012; Spruijt et al, 2013; Diotel et al, 2017), MeCP2 (methyl-CpG-binding protein 2) has similar affinity to 5hmC and 5mC (Mellén et al, 2012). However, the 5hmC level is negatively correlated with MeCP2 abundance.…”

“…Global detection of 5hmC has been carried out in human, mouse, zebrafish, and Xenopus (Globisch et al, 2010; Munzel et al, 2010; Chen and Riggs, 2011; Jin et al, 2011; Song et al, 2011; Szulwach et al, 2011a,b; Almeida et al, 2012; Han et al, 2016; Diotel et al, 2017). These studies showed that the dynamics and abundance of 5hmC are cell type-dependent and developmentally regulated.…”

Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders

“…Loss of demethylation by active mechanisms should also be considered, such as the activation of the GADD45B demethylase in the DG cells during adult neurogenesis [49] or the transformation of 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) by enzymes of the TET family [50]. 5-hmC is enriched in adult neurons compared to NSPCs of the SVZ in the mouse developing brain and colocalize with MeCP2 and with the active chromatin histone modification H3K4me2 in mouse neurons [51]. Another mechanism by which CpG methylation results in transcriptional silence is by binding to methyl-CpG-binding proteins that recruit several chromatin remodelling proteins.…”

DNA Methylation program in normal and alcohol-induced thinning cortex

“…5mC subsequently declines as migration begins from the upper limits of the VZ and through the IZ and enters a second cycle of up-regulation in the upper cortical layers as maturing neurons prepare for synaptogenesis. 5hmC, which functions as a bivalent or activating epigenetic mark (Chen, Damayanti, Irudayaraj, Dunn, & Zhou, 2014; Diotel et al, 2016; Resendiz, Chen, Öztürk, & Zhou, 2013), appears as differentiation proceeds and peaks when neurons are specified. In the VZ, where cortical proliferation (Ki67+) and neurogenesis progress and in SVZ where neural specification begins (Tbr2+ cell bodies), 5mC is prominent in the cells with mostly ellipsoidal-shaped nuclei, while 5hmC weakly appears in a subpopulation of the VZ and SVZ.…”