| 1 | Transl Psychiatry 2012 -1 2: e159 |
|---|---|
| PMID | 22948384 |
| Title | Upregulation of TET1 and downregulation of APOBEC3A and APOBEC3C in the parietal cortex of psychotic patients. |
| 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. |
| SCZ Keywords | schizophrenia |
| 2 | Schizophr. Res. 2013 Oct 150: 312-8 |
| PMID | 23938174 |
| Title | DNA-methylation gene network dysregulation in peripheral blood lymphocytes of schizophrenia patients. |
| Abstract | The epigenetic dysregulation of the brain genome associated with the clinical manifestations of schizophrenia (SZ) includes altered DNA promoter methylation of several candidate genes. We and others have reported that two enzymes that belong to the DNA-methylation/demethylation network pathways-DNMT1 (DNA-methyltransferase) and ten-eleven translocator-1(TET1) methylcytosine deoxygenase are abnormally increased in corticolimbic structures of SZ postmortem brain. The objective of this study was to investigate whether the expression of these components of the DNA-methylation-demethylation pathways known to be altered in the brain of SZ patients are also altered in peripheral blood lymphocytes (PBL). The data show that increases in DNMT1 and TET1 and in glucocorticoid receptor (GCortR) and brain derived neurotrophic factor (BDNF) mRNAs in PBL of SZ patients are comparable to those reported in the brain of SZ patients. The finding that the expressions of DNMT1 and TET1 are increased and SZ candidate genes such as BDNF and GCortR are altered in the same direction in both the brain and PBL together with recent studies showing highly correlated patterns of DNA methylation across the brain and blood, support the hypothesis that a common epigenetic dysregulation may be operative in the brain and peripheral tissues of SZ patients. |
| SCZ Keywords | schizophrenia |
| 3 | Alcohol. Clin. Exp. Res. 2013 Mar 37: 417-24 |
| PMID | 22958170 |
| Title | DNA methylation/demethylation network expression in psychotic patients with a history of alcohol abuse. |
| Abstract | Recent studies suggest that protracted and excessive alcohol use induces an epigenetic dysregulation in human and rodent brains. We recently reported that DNA methylation dynamics are altered in brains of psychotic (PS) patients, including schizophrenia and bipolar disorder patients. Because PS patients are often comorbid with chronic alcohol abuse, we examined whether the altered expression of multiple members of the DNA methylation/demethylation network observed in postmortem brains of PS patients was modified in PS patients with a history of chronic alcohol abuse. DNA-methyltransferase-1 (DNMT1) mRNA-positive neurons were counted in situ in prefrontal cortex samples obtained from the Harvard Brain Tissue Resource Center, Belmont, MA. 10-11-translocation (TETs 1, 2, 3), apolipoprotein B editing complex enzyme (APOBEC-3C), growth and DNA-damage-inducible protein 45? (GADD45?), and methyl-binding domain protein-4 (MBD4) mRNAs were measured by quantitative real-time polymerase chain reaction in inferior parietal cortical lobule samples obtained from the Stanley Foundation Neuropathology Consortium, Bethesda, MD. We observed an increase in DNMT1 mRNA-positive neurons in PS patients compared with non-PS subjects. In addition, there was a pronounced decrease in APOBEC-3C and a pronounced increase in GADD45? and TET1 mRNAs in PS patients with no history of alcohol abuse. In PS patients with a history of chronic alcohol abuse, the numbers of DNMT1-positive neurons were not increased significantly. Furthermore, the decrease in APOBEC-3C mRNA was less pronounced, while the increase in TET1 mRNA had a tendency to be potentiated in those PS patients that were chronic alcohol abusers. GADD45? and MBD4 mRNAs were not influenced by alcohol abuse. The effect of chronic alcohol abuse on DNA methylation/demethylation network enzymes cannot be attributed to confounding demographic variables or to the type and dose of medication used. Based on these results, we hypothesize that PS patients may abuse alcohol as a potential attempt at self-medication to normalize altered DNA methylation/demethylation network pathways. However, before accepting this conclusion, we need to study alterations in the DNA methylation/demethylation pathways and the DNA methylation dynamics in a substantial number of alcoholic PS and non-PS patients. Additional investigation may also be necessary to determine whether the altered DNA methylation dynamics are direct or the consequence of an indirect interaction of alcohol with the neuropathogenetic mechanisms underlying psychosis. |
| SCZ Keywords | schizophrenia |
| 4 | Prog Mol Biol Transl Sci 2014 -1 128: 89-101 |
| PMID | 25410542 |
| Title | Modeling the molecular epigenetic profile of psychosis in prenatally stressed mice. |
| Abstract | Based on postmortem brain studies, our overarching epigenetic hypothesis is that chronic schizophrenia (SZ) is a psychopathological condition involving dysregulation of the dynamic equilibrium among DNA methylation/demethylation network components and the expression of SZ target genes, including GABAergic and glutamatergic genes. SZ has a natural course, starting with a prodromal phase, a first episode that occurs in adolescents or in young adults, and later deterioration over the adult years. Hence, the epigenetic status at each neurodevelopmental stage of the disease cannot be studied just in postmortem brain of chronic SZ patients, but requires the use of neurodevelopmental animal models. We have directed the focus of our research toward studying the epigenetic signature of the SZ brain in the offspring of dams stressed during pregnancy (PRS mice). Adult PRS mice have behavioral deficits reminiscent of behaviors observed in psychotic patients. The adult PRS brain, like that of postmortem chronic SZ patients, is characterized by a significant increase in DNA methyltransferase 1, Tet methylcytosine dioxygenase 1 (TET1), 5-methylcytosine, and 5-hydroxymethylcytosine at SZ candidate gene promoters and a reduction in the expression of glutamatergic and GABAergic genes. In PRS mice, measurements of epigenetic biomarkers for SZ can be assessed at different stages of development with the goal of further elucidating the pathophysiology of this disease and predicting treatment responses at specific stages of the illness, with particular attention to early detection and possibly early intervention. |
| SCZ Keywords | schizophrenia |
| 5 | Schizophr. Res. 2015 Sep 167: 35-41 |
| PMID | 25476119 |
| Title | DNA-methyltransferase1 (DNMT1) binding to CpG rich GABAergic and BDNF promoters is increased in the brain of schizophrenia and bipolar disorder patients. |
| Abstract | The down regulation of glutamic acid decarboxylase67 (GAD1), reelin (RELN), and BDNF expression in brain of schizophrenia (SZ) and bipolar (BP) disorder patients is associated with overexpression of DNA methyltransferase1 (DNMT1) and ten-eleven translocase methylcytosine dioxygenase1 (TET1). DNMT1 and TET1 belong to families of enzymes that methylate and hydroxymethylate cytosines located proximal to and within cytosine phosphodiester guanine (CpG) islands of many gene promoters, respectively. Altered promoter methylation may be one mechanism underlying the down-regulation of GABAergic and glutamatergic gene expression. However, recent reports suggest that both DNMT1 and TET1 directly bind to unmethylated CpG rich promoters through their respective Zinc Finger (ZF-CXXC) domains. We report here, that the binding of DNMT1 to GABAergic (GAD1, RELN) and glutamatergic (BDNF-IX) promoters is increased in SZ and BP disorder patients and this increase does not necessarily correlate with enrichment in promoter methylation. The increased DNMT1 binding to these promoter regions is detected in the cortex but not in the cerebellum of SZ and BP disorder patients, suggesting a brain region and neuron specific dependent mechanism. Increased binding of DNMT1 positively correlates with increased expression of DNMT1 and with increased binding of MBD2. In contrast, the binding of TET1 to RELN, GAD1 and BDNF-IX promoters failed to change. These data are consistent with the hypothesis that the down-regulation of specific GABAergic and glutamatergic genes in SZ and BP disorder patients may be mediated, at least in part, by a brain region specific and neuronal-activity dependent DNMT1 action that is likely independent of its DNA methylation activity. |
| SCZ Keywords | schizophrenia |
| 6 | Transl Psychiatry 2016 -1 6: e711 |
| PMID | 26756904 |
| Title | Behavioral and molecular neuroepigenetic alterations in prenatally stressed mice: relevance for the study of chromatin remodeling properties of antipsychotic drugs. |
| Abstract | We have recently reported that mice born from dams stressed during pregnancy (PRS mice), in adulthood, have behavioral deficits reminiscent of behaviors observed in schizophrenia (SZ) and bipolar (BP) disorder patients. Furthermore, we have shown that the frontal cortex (FC) and hippocampus of adult PRS mice, like that of postmortem chronic SZ patients, are characterized by increases in DNA-methyltransferase 1 (DNMT1), ten-eleven methylcytosine dioxygenase 1 (TET1) and exhibit an enrichment of 5-methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC) at neocortical GABAergic and glutamatergic gene promoters. Here, we show that the behavioral deficits and the increased 5MC and 5HMC at glutamic acid decarboxylase 67 (Gad1), reelin (Reln) and brain-derived neurotrophic factor (Bdnf) promoters and the reduced expression of the messenger RNAs (mRNAs) and proteins corresponding to these genes in FC of adult PRS mice is reversed by treatment with clozapine (5 mg kg(-1) twice a day for 5 days) but not by haloperidol (1 mg kg(-1) twice a day for 5 days). Interestingly, clozapine had no effect on either the behavior, promoter methylation or the expression of these mRNAs and proteins when administered to offspring of nonstressed pregnant mice. Clozapine, but not haloperidol, reduced the elevated levels of DNMT1 and TET1, as well as the elevated levels of DNMT1 binding to Gad1, Reln and Bdnf promoters in PRS mice suggesting that clozapine, unlike haloperidol, may limit DNA methylation by interfering with DNA methylation dynamics. We conclude that the PRS mouse model may be useful preclinically in screening for the potential efficacy of antipsychotic drugs acting on altered epigenetic mechanisms. Furthermore, PRS mice may be invaluable for understanding the etiopathogenesis of SZ and BP disorder and for predicting treatment responses at early stages of the illness allowing for early detection and remedial intervention. |
| SCZ Keywords | schizophrenia |