Abstract
Increasing evidence suggests that epigenetic dysfunction may account for the alteration of gene transcription present in neuropsychiatric disorders such as schizophrenia (SZ), bipolar disorder (BP) and autism. Here, we studied the expression of the ten-eleven translocation (TET) gene family and activation-induced deaminase/apolipoprotein B mRNA-editing enzymes (AID/APOBEC) in the inferior parietal lobule (IPL) (BA39-40) and the cerebellum of psychotic (PSY) patients, depressed (DEP) patients and nonpsychiatric (CTR) subjects obtained from the Stanley Foundation Neuropathology Consortium Medical Research Institute. These two sets of enzymes have a critical role in the active DNA demethylation pathway. The results show that TET1, but not TET2 and TET3, mRNA and protein expression was increased (two- to threefold) in the IPL of the PSY patients compared with the CTR subjects. TET1 mRNA showed no change in the cerebellum. Consistent with the increase of TET1, the level of 5-hydroxymethylcytosine (5hmC) was elevated in the IPL of PSY patients but not in the other groups. Moreover, higher 5hmC levels were detected at the glutamic acid decarboxylase67 (GAD67) promoter only in the PSY group. This increase was inversely related to the decrease of GAD67 mRNA expression. Of 11 DNA deaminases measured, APOBEC3A mRNA was significantly decreased in the PSY and DEP patients, while APOBEC3C was decreased only in PSY patients. The other APOBEC mRNA studied failed to change. Increased TET1 and decreased APOBEC3A and APOBEC3C found in this study highlight the possible role of altered DNA demethylation mechanisms in the pathophysiology of psychosis.
Highlights
Epigenetic modifications of chromatin, including methylation of genomic DNA, and acetylation or methylation of histones, have a critical role in orchestrating the expression of specific genes in postmitotic neurons
We found an approximately twofold increase in the expression of TET1 mRNA in the PSY group compared with the CTR group (P 1⁄4 0.001, Dunnett’s correction; P 1⁄4 0.002 Bonferroni correction)
The major finding presented in this paper is that TET1 is markedly increased in the parietal cortex of PSY patients and this increase associates with an increase of 5hmC level at genomic DNA and with specific increases of 5hmC levels at glutamic acid decarboxylase67 (GAD67) (Figure 4) and BDNF4 promoters in proximity of their transcriptional star sites (TSS)
Summary
Epigenetic modifications of chromatin, including methylation of genomic DNA, and acetylation or methylation of histones, have a critical role in orchestrating the expression of specific genes in postmitotic neurons. This theory has been supported by several independent and interesting findings showing that 5mC mark on promoter CpG-rich regions of specific genes can be oxidized to form 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) proteins in mammalian brain.[20,21,22,23,24] Recent evidence suggests that TET proteins, important contributors in DNA demethylation process, have essential roles in neurodevelopment and aging[25] and are involved in human cancers.[26]
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