Reelin promoter hypermethylation in schizophrenia

Abstract

Reelin mRNA and protein levels are reduced by Ϸ50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. In addition, the mRNA encoding the methylating enzyme, DNA methyltransferase 1, is up-regulated in the same neurons that coexpress reelin and glutamic acid decarboxylase 67. We have analyzed the extent and pattern of methylation within the CpG island of the reelin promoter in genomic DNA isolated from cortices of schizophrenia patients and nonpsychiatric subjects. Ten (The Stanley Foundation Neuropathology Consortium) and five (Harvard Brain Collection) schizophrenia patients and an equal number of nonpsychiatric subjects were selected from each brain collection. Genomic DNA was isolated, amplified (from base pair ؊527 to base pair ؉322) after bisulphite treatment, and sequenced. The results show that within the promoter region there were interesting regional variations. There was increased methylation at positions ؊134 and ؊139, which is particularly important for regulation, because this portion of the promoter is functionally competent based on transient transfection assays. This promoter region binds a protein present in neuronal precursor nuclear extracts that express very low levels of reelin mRNA; i.e., an oligonucleotide corresponding to this region and that contains methylated cytosines binds more tightly to extracts from nonexpressing cells than the nonmethylated counterpart. Collectively, the data show that this promoter region has positive and negative properties and that the function of this complex cis element relates to its methylation status.DNA methyltransferase ͉ epigenetics ͉ gene regulation ͉ methylation ͉ psychiatric disorder S chizophrenia is a devastating disorder with a populationwide morbidity approaching 1%. The genetics of the disease are perhaps one of the most studied facets of schizophrenia, but the results of multiple linkage analyses have not provided a clarification of underlying etiological factors that define the symptomatology of the disease (1, 2). However, insight has come from recent reports that examined biological markers that appear to be aberrantly regulated in postmortem brains of patients diagnosed with schizophrenia (3-5). It was noted that among Ͼ100 different markers examined, reelin and glutamic acid decarboxylase (GAD) 67 are the most abnormal in the context of schizophrenia and bipolar illness (6). These two mRNAs and their cognate proteins are selectively coexpressed in GABAergic neurons of the mammalian cortex. The observation that reelin and GAD 67 are down-regulated has been one of the more consistently replicated findings observed in postmortem cortex from schizophrenia patients (SZP). We previously reported reelin mRNA and protein levels are quantitatively reduced by Ϸ50% in various cortical structures of postmortem brain from SZP and bipolar patients (3, 4). The results obtained with respect to reelin were independently confirmed immunohistochemically in the hippocampus (7) and ...

The social environment and the epigenome

“…The gene encoding REELIN a protein involved in neuronal development and synaptogenesis, which is implicated in long-term memory was found to be methylated in brains of schizophrenia patients. The methylation of REELIN was correlated with its reduced expression and increased DNMT1 expression in GABAergic neurons in the prefrontal cortex Costa et al, 2002Costa et al, , 2003Grayson et al, 2005;Veldic et al, 2007].…”

“…SAM was shown to inhibit active demethylation [Detich et al, 2003b] and to stimulate methylation [Pascale et al, 1991]. Methionine treatment was previously shown to increase SAM and DNA methylation levels in the brain Grayson et al, 2005]. Methionine treatment of the offspring of High LG maternal care changed the DNA methylation state of GR exon 1 7 promoter and expression of GR in the hippocampus as well as increased their stress responsiveness and reduced the time that these animals spent in the open field.…”

Histone deacetylases 1 and 2 are expressed at distinct stages of neuro‐glial development

“…The development and function of the nervous system appears to be particularly sensitive to disruptions in epigenetic gene regulation, leading to syndromes associated with mental retardation (reviewed in Egger et al, 2004), as well as complex psychiatric disorders such as schizophrenia (Veldic et al, 2004;Grayson et al, 2005). The nervous system is unique in the remarkably complex patterning of the brain that must be established, while still maintaining a large degree of plasticity in order for the brain to respond to a changing environment.…”

Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan

“…An important role of DNA methylation in the nervous system is indicated by Rett syndrome, a neurodevelopmental disorder caused by mutations in MeCP2, a transcriptional repressor that binds to methylated CpGs (Amir and Zoghbi, 2000;Guy et al, 2001). Also, changes in methylation of the reelin promoter have been correlated with schizophrenia (Grayson et al, 2005).…”