Hypermethylation of the reelin (RELN) promoter region and the reduced levels of its messenger RNA and protein have been implicated in the pathophysiology of schizophrenia. We intended a technical replication of recent studies that observed hypermethylation of CpG or CpNpG sites in the RELN promoter region in the brain of schizophrenic patients.
The DNA methylation status of the promoter region of RELN was examined by using the pyrosequencing method in the prefrontal cortices of 14 patients with schizophrenia and 13 control subjects.
All of the CpG and two proposed CpNpG sites analyzed showed no detectable DNA methylation (< 5%) in both control subjects and patients with schizophrenia. No detectable DNA methylation was observed in both gray and white matter, excluding the possibility of cellular heterogeneity of start materials.
We did not confirm the hypermethylation of the RELN promoter region in the brains of schizophrenic patients, suggested in the previous studies.
"We identified over one hundred CpG sites with aberrant DNA methylation in schizophrenia in this genome-wide DNA methylation profiling study performed in a large cohort of 106 patients with schizophrenia and 110 non-psychiatric controls. To date, 11 DNA methylation studies were conducted on schizophrenia using postmortem brains, but the sample sizes of these studies were relatively small (~35 patients with schizophrenia) (Abdolmaleky et al., 2005, 2006, 2011; Grayson et al., 2005; Iwamoto et al., 2005; Dempster et al., 2006; Tamura et al., 2007; Mill et al., 2008; Tochigi et al., 2008; Tolosa et al., 2010; Wockner et al., 2014). "
[Show abstract][Hide abstract] ABSTRACT: Background: Schizophrenia is a complex psychiatric disorder with a lifetime morbidity rate of 0.5–1.0%. The pathophysiology of schizophrenia still remains obscure. Accumulating evidence indicates that DNA methylation, which is the addition of a methyl group to the cytosine in a CpG dinucleotide, might play an important role in the pathogenesis of schizophrenia.
Methods: To gain further insight into the molecular mechanisms underlying schizophrenia, a genome-wide DNA methylation profiling (27,578 CpG dinucleotides spanning 14,495 genes) of the human dorsolateral prefrontal cortex (DLPFC) was conducted in a large cohort (n = 216) of well characterized specimens from individuals with schizophrenia and non-psychiatric controls, combined with an analysis of genetic variance at ~880,000 SNPs.
Results: Aberrant DNA methylation in schizophrenia was identified at 107 CpG sites at 5% Bonferroni correction (p < 1.99 × 10−6). Of these significantly altered sites, hyper-DNA methylation was observed at 79 sites (73.8%), mostly in the CpG islands (CGIs) and in the regions flanking CGIs (CGI: 31 sites; CGI shore: 35 sites; CGI shelf: 3 sites). Furthermore, a large number of cis-methylation quantitative trait loci (mQTL) were identified, including associations with risk SNPs implicated in schizophrenia.
Conclusions: These results suggest that altered DNA methylation might be involved in the pathophysiology and/or treatment of schizophrenia, and that a combination of epigenetic and genetic approaches will be useful to understanding the molecular mechanism of this complex disorder.
Frontiers in Genetics 08/2014; 5:280. DOI:10.3389/fgene.2014.00280
"Furthermore, the schizophrenia candidate gene involved in synaptic plasticity, reelin, may be downregulated in schizophrenia perhaps via increased promoter DNA methylation (Abdolmaleky et al., 2005; Fatemi et al., 2005; Grayson et al., 2005). However, inconsistent results from post mortem studies (Dempster et al., 2006; Lintas and Persico, 2010; Mill et al., 2008; Tochigi et al., 2008) suggest that the DNA methylation status of a specific promoter is the result of a dynamic equilibrium resulting from the summation of DNMT activity and DNA demethylation factors (Dong et al., 2010; Szyf, 2010). Many of the initial studies of epigenetic changes in psychosis and schizophrenia indicated an increase in either restrictive chromatin marks, such as DNA methylation or histone modifications, or increases in the enzymes that catalyze the reactions that lead to their formation. "
[Show abstract][Hide abstract] ABSTRACT: Over the last several years proteins involved in base excision repair (BER) have been implicated in active DNA demethylation. We review the literature supporting BER as a means of active DNA demethylation, and explain how the various components function and cooperate to remove the potentially most enduring means of epigenetic gene regulation. Recent evidence indicates that the same pathways implicated during periods of widespread DNA demethylation, such as the erasure of methyl marks in the paternal pronucleus soon after fertilization, are operational in post-mitotic neurons. Neuronal functional identities, defined here as the result of a combination of neuronal subtype, location, and synaptic connections are largely maintained through DNA methylation. Chronic mental illnesses, such as schizophrenia, may be the result of both altered neurotransmitter levels and neurons that have assumed dysfunctional neuronal identities. A limitation of most current psychopharmacological agents is their focus on the former, while not addressing the more profound latter pathophysiological process. Previously, it was believed that active DNA demethylation in post-mitotic neurons was rare if not impossible. If this were the case, then reversing the factors that maintain neuronal identity, would be highly unlikely. The emergence of an active DNA demethylation pathway in the brain is a reason for great optimism in psychiatry as it provides a means by which previously pathological neurons may be reprogrammed into a more favorable role. Agents targeting epigenetic processes have shown much promise in this regard, and may lead to substantial gains over traditional pharmacological approaches.
"In addition, the gene encoding DNA methyltransferase 1 (DNMT1) was found to be overexpressed in GABAergic interneurons in postmortem brain samples from schizophrenia patients . However, other groups found no correlation between schizophrenia and RELN promoter methylation levels in (pre)frontal cortices [49,50]. "
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia is a severe psychiatric disease affecting about 1% of the world's population, with significant effects on patients and society. Genetic studies have identified several candidate risk genes or genomic regions for schizophrenia, and epidemiological studies have revealed several environmental risk factors. However, the etiology of schizophrenia still remains largely unknown. Epigenetic mechanisms such as DNA methylation and histone modifications can explain the interaction between genetic and environmental factors at the molecular level, and accumulating evidence suggests that such epigenetic alterations are involved in the pathophysiology of schizophrenia. However, replication studies to validate previous findings and investigations of the causality of epigenetic alterations in schizophrenia are needed. Here, we review epigenetic studies of schizophrenia patients using postmortem brains or peripheral tissues, focusing mainly on DNA methylation. We also highlight the recent progress and challenges in characterizing the potentially complex and dynamic patterns of epigenomic variations. Such studies are expected to contribute to our understanding of schizophrenia etiology and should provide novel opportunities for the development of therapeutic drugs.
Genome Medicine 12/2012; 4(12):96. DOI:10.1186/gm397 · 5.34 Impact Factor
Nicolás Navasa, Itziar Martin-Ruiz, Estíbaliz Atondo, James D. Sutherland, Miguel Angel Pascual-Itoiz, Ana Carreras-González, Hooman Izadi, Julen Tomás-Cortázar, Furkan Ayaz, Natalia Martin-Martin, Iviana M Torres, Rosa Barrio, Arkaitz Carracedo, Elias R. Olivera, Mercedes Rincón, Juan Anguita
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.