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

Abstract

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.

5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma

“…Gene body 5mC was neither strongly nor consistently associated with gene expression. With respect to hydroxymethylation, we identified gene expression to be most strongly associated with 5hmC targeting gene body regions, in keeping with prior reports [ 12 , 17 , 38 ]. At the gene-specific level, using two separate approaches (examining regions of high 5hmC abundance as well as DHMRs), we observed a highly significant striking pattern of positive correlation between 5hmC and gene expression for genes that are highly expressed in the IDH1 mt cohort (Group 1 probes).…”

A role for activity‐dependent epigenetics in the development and treatment of major depressive disorder

“…Indeed, in the context of major depression, 5-hmC levels remain relatively unchanged in human patients compared with controls with the exception of key genes where it is associated with changes in gene expression. 74 The expression and activity of DNA methyltransferases (DNMT) has also been shown to increase in multiple models of cellular activity, and is significantly altered in patients suffering from a depressive episode. 75 For example, high frequency stimulation of medial prefrontal cortex (mPFC) slices from mice results in a rapid increase in total DNMT levels, and in the hippocampus, the canonical de novo methyltransferases DNMT3a and 3b are increased after fear conditioning.…”

Myosin XVI in the Nervous System

“…The predominant expression of Myo16 in neural tissues suggests its importance in the proper functioning of the brain, mainly during development but also in adulthood. In line with this, the alterations of the human MYO16 ; either s ingle n uclear p olymorphisms (SNPs), deletions or epigenetic modifications are associated with neurodegenerative and neuropsychiatric disorders, including schizophrenia, a utism s pectrum d isorder (ASD), b i p olar disorder subtype II (BP-II) and m ajor d epressive d isorder (MDD) ( Table 1 ) [ 21 , 22 , 23 , 24 , 25 ]. In addition to the association of the MYO16 gene to neurological disorders, many binding partners of Myo16 identified so far are central to normal brain functioning [ 31 ].…”