5hmC In Brain Research Articles

Gene-body 5-hydroxymethylation is associated with gene expression changes in the prefrontal cortex of depressed individuals

5-Hydroxymethylcytosine (5hmC) is a recently characterized epigenetic mark that is particularly abundant in brain tissue and that regulates gene transcription. We have recently begun to understand the important role of 5hmC in brain development, plasticity and disease, but there are currently little data on 5hmC alterations in psychiatric illnesses. Here we report what we believe to be the first genome-wide analysis of 5hmC in the depressed brain. Using AbaSI sequencing, we investigated 5hmC in the prefrontal cortex of depressed (N=19) and psychiatrically healthy controls (N=19). Consistent with previous global 5hmC analyses in other phenotypes, and likely owing to the inter-individual variability in 5hmC content, the distribution of 5hmC across chromosomes and genomic features was not different between groups. We did, however, find 550 CpGs with suggestive evidence of differential hydroxymethylation. Of these, we validated CpGs in the gene body of myosin XVI (MYO16) and insulin-degrading enzyme using targeted oxidative bisulfite sequencing. Furthermore, the enrichment of 5hmC was also associated with changes in the expression of these two genes in depressed suicides. Together, our results present a novel mechanism linking increased 5hmC to depression and provide a framework for future research in this field.

The 5-Hydroxymethylcytosine (5hmC) Reader UHRF2 Is Required for Normal Levels of 5hmC in Mouse Adult Brain and Spatial Learning and Memory

UHRF2 has been implicated as a novel regulator for both DNA methylation (5mC) and hydroxymethylation (5hmC), but its physiological function and role in DNA methylation/hydroxymethylation are unknown. Here we show that in mice, UHRF2 is more abundantly expressed in the brain and a few other tissues. Uhrf2 knock-out mice are viable and fertile and exhibit no gross defect. Although there is no significant change of DNA methylation, the Uhrf2 null mice exhibit a reduction of 5hmC in the brain, including the cortex and hippocampus. Furthermore, the Uhrf2 null mice exhibit a partial impairment in spatial memory acquisition and retention. Consistent with the phenotype, gene expression profiling uncovers a role for UHRF2 in regulating neuron-related gene expression. Finally, we provide evidence that UHRF2 binds 5hmC in cells but does not appear to affect the TET1 enzymatic activity. Together, our study supports UHRF2 as a bona fide 5hmC reader and further demonstrates a role for 5hmC in neuronal function.

Characterizing 5-hydroxymethylcytosine in human prefrontal cortex at single base resolution.

BackgroundThe recent discovery that methylated cytosines are converted to 5-hydroxymethylated cytosines (5hmC) by the family of ten-eleven translocation enzymes has sparked significant interest on the genomic location, the abundance in different tissues, the putative functions, and the stability of this epigenetic mark. 5hmC plays a key role in the brain, where it is particularly abundant and dynamic during development.ResultsHere, we comprehensively characterize 5hmC in the prefrontal cortices of 24 subjects. We show that, although there is inter-individual variability in 5hmC content among unrelated individuals, approximately 8 % of all CpGs on autosomal chromosomes contain 5hmC, while sex chromosomes contain far less. Our data also provide evidence suggesting that 5hmC has transcriptional regulatory properties, as the density of 5hmC was highest in enhancer regions and within exons. Furthermore, we link increased 5hmC density to histone modification binding sites, to the gene bodies of actively transcribed genes, and to exon-intron boundaries. Finally, we provide several genomic regions of interest that contain gender-specific 5hmC.ConclusionsCollectively, these results present an important reference for the growing number of studies that are interested in the investigation of the role of 5hmC in brain and mental disorders.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1875-8) contains supplementary material, which is available to authorized users.

From development to diseases: The role of 5hmC in brain

Epigenetic modulations play essential roles in diverse biological processes. During the past several years, DNA demethylation has been discovered in embryonic and postnatal development. Although some potential functions of DNA methylation have been demonstrated already, many questions remain in terms of unveiling the role of 5hmC; whether it serves either merely as an intermediate of DNA demethylation or as a stable epigenetic marker. 5-hydroxymethylcytosine (5hmC) is proved to be not merely serving as an intermediate of DNA demethylation, but also acts as a stable epigenetic marker. This review summarizes the current knowledge of the function of 5hmC in brain with the focus on the neuronal activity, neurodevelopment, aging, and neurological diseases.