An upregulation of DNA-methyltransferase 1 and 3a expressed in telencephalic GABAergic neurons of schizophrenia patients is also detected in peripheral blood lymphocytes

Abstract

Several lines of schizophrenia (SZ) research suggest that a functional downregulation of the prefrontal cortex GABAergic neuronal system is mediated by a promoter hypermethylation, presumably catalyzed by an increase in DNA-methyltransferase-1 (DNMT-1) expression. This promoter hypermethylation may be mediated not only by DNMT-1 but also by an entire family of de novo DNA-methyltransferases, such as DNA-methyltransferase-3a (DNMT-3a) and -3b (DNMT-3b). To verify the existence of an overexpression of DNMT-3a and DNMT-3b in the brain of schizophrenia patients (SZP), we compared their mRNA expression in Brodmann’s area 10 (BA10) and in the caudate nucleus and putamen obtained from the Harvard Brain Tissue Resource Center (Belmont, MA) from both nonpsychiatric subjects (NPS) and SZP. Our results demonstrate that DNMT-3a and DNMT-1 are expressed and co-localize in distinct GABAergic neuron populations whereas DNMT-3b mRNA is virtually undetectable. We also found that unlike DNMT-1, which is frequently overexpressed in telencephalic GABAergic neurons of SZP, DNMT-3a mRNA is overexpressed only in layers I and II GABAergic interneurons of BA10. To ascertain whether these DNMT expression differences observed in brain tissue could also be detected in peripheral tissues, we studied whether DNMT-1 and DNMT-3a mRNAs were overexpressed in peripheral blood lymphocytes (PBL) of SZP. Both DNMT-1 and DNMT-3a mRNAs are expressed in the PBL and although DNMT-3a mRNA levels in the PBL are approximately 1/10 of those of DNMT-1, the comparison of the PBL content in NPS and SZP showed a highly significant 2-fold increase of both DNMT-1 and DNMT-3a mRNA in SZP. These changes were unaffected by the dose, the duration, or the type of antipsychotic treatment. The upregulation of DNMT-1 and to a lesser extent that of DNMT-3a mRNA in and PBL of SZP supports the concept that this readily available peripheral cell type can express an epigenetic variation of specific biomarkers relevant to SZ morbidity. Hence, PBL studies may become useful to investigate a diagnostic epigenetic marker of SZ morbidity.

Epigenetic Treatments for Cognitive Impairments

“…Consistent with this hypothesis, patients with schizophrenia exhibit hypermethylation at the synaptic plasticity gene reelin in the cortex, which is associated with decreased reelin expression (Grayson et al, 2005). Additionally, post-mortem samples from schizophrenic patients have revealed an overexpression of DNMT1 and DNMT3a in GABAergic neurons (Zhubi et al, 2009), which is consistent with the observation that DNMT1 regulates reelin methylation in vivo (Noh et al, 2005).…”

Growth Arrest and DNA-Damage-Inducible, Beta (GADD45b)-Mediated DNA Demethylation in Major Psychosis

“…While several studies from our group have pointed to a hypermethylating milieu in the brains of psychotic subjects (Grayson et al, 2005;Guidotti et al, 2011Guidotti et al, , 2007Veldic et al, 2005Veldic et al, , 2007Zhubi et al, 2009;Ruzicka et al, 2007), others found decreased DNA methylation at particular genes (Abdolmaleky et al, 2006) or overall dysfunctional methylation networks comprised of both increases and decreases in methylation (Mill et al, 2008). Further, several studies have failed to replicate DNA methylation changes at particular genes (Tochigi et al, 2008;Mill et al, 2008;Dempster et al, 2006).…”

“…This is because the majority of previous studies have reported increases in factors associated with a restrictive chromatin state, such as increased DNMT expression (Veldic et al, 2004(Veldic et al, , 2005Zhubi et al, 2009;Ruzicka et al, 2007), DNA promoter methylation (Grayson et al, 2005;Abdolmaleky et al, 2005), and repressive histone modifications (Gavin et al, 2009a, b;Benes et al, 2007; in psychotic patients. These abnormalities are hypothesized to cause the muchreplicated reductions in GABAergic gene expression in psychosis (Benes et al, 2007;Akbarian et al, 1995;Fatemi et al, 2005;Hashimoto et al, 2008;Costa et al, 2004;Guidotti et al, 2000).…”

The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders

“…Unlike DNMT1, DNMT3A is overexpressed only in layers I and II (Zhubi et al, 2009). DNMT3B mRNA was examined and not detected in any cortical layer.…”