Epigenetic Mechanisms in Schizophrenia

Literature review

Over the years, a wide range of studies has been carried out on the subject of epigenetics and the epigenetic mechanism of diseases. Broadly, the term epigenetics refers to the range of mechanisms in genome function that do not solely culminate from the DNA sequence itself (Christopher, Kyle & Katz, 2017). The epigenetic apparatus plays a crucial role in the control of hemostasis and normal development. Further, it provides the means through which an organism can integrate and also react to the environment.

The study of the epigenetic mechanism of schizophrenia has generated remarkable information that can be utilized in the management, treatment, and prevention of this disorder.

Shorter and Miller (2015) noted that at a neuro-pharmacological level, the brain of a person with schizophrenia exhibits a decrease in the number as well as the complexity of various neuronal connections in the cortex. These changes indicate abnormal synaptic pruning in the final stages of neurodevelopment. Shorter and Miller (2015) also made it clear that a reduction in dendritic complexity is synonymous with the cognitive deficits exemplified in schizophrenia.

Evidence shows that irrespective of the lack of unifying neuropathology, a significant proportion of schizophrenia cases are attributed to alterations in gene expression in various sections of the brain including the cerebral cortex (Akbarian, 2014). These alterations often involve transcripts that are crucial for oligodendrocyte myelination and function. Unfortunately, it is not clear if these transcriptional changes are directly associated with the underlying causes or secondary events in the developmental processes of schizophrenia (Akbarian, 2014). Since the transcriptional mechanisms are closely associated with histone modification and chromatin remodeling machinery in the nucleus, it would not be surprising if some of the genes affected by alterations in schizophrenia demonstrated significant related changes in the epigenetic architecture of their repressor elements, enhancers, promoters, and other regulatory sequences (Akbarian, 2014).

Föcking et al. (2019) pointed out that post-modern studies have revealed significant brain-related abnormalities in persons with schizophrenia. These abnormalities include dysregulation of proteomes and transcriptomes in temporal and pre-frontal cortex oligodendrocytes. Similarly, abnormalities have been reported in key proteins that are involved in neuronal function. Post mortem analyses of the brain from schizophrenia patients show significant expression changes in these proteins. Some of these proteins include neurotransmitter pathway enzymes and ion channels. Shorter and Miller (2015), for instance, noted that there is a strong correlation between dopamine signaling pathways and schizophrenia. However, genomewide association research studies have not loci containing dopamine genes. Candidate gene mapping and quantitative trait locus have led to the identification of strong candidate genes including NRG1, D1SC1, and GABA-receptor subunits. Unfortunately, it is hard to replicate these studies due to the variability of the patient population, the insignificant effect sizes of the risk genes, environmental factors and epistasis (Shorter & Miller, 2015).

Evidence from various studies has implicated DNA methylation in the development of long-term phenotypical changes associated with schizophrenia. Some of these phenotypical changes include the dysregulation of DNA methylation, cell differentiation, genetic imprinting, and inactivation of the X-chromosome (Roth, Lubin, Sodhi & Kleinman, 2009). The phenotypical outcomes in these cases are resultant factors of DNA methylation programming that occurs in the early stages of development. Notably, the onset of schizophrenia is experienced during adolescence and early adulthood stages. Environmental factors play an integral role in the development of this disorder (Roth, Lubin, Sodhi & Kleinman, 2009).

Experimental data

In a genome-wide study, as noted by Föcking et al., (2019), 128 common variants in 108 different loci were identified. These variations were shown to cumulatively increase the risk of the disease. The genes identified in this study are involved in various neurological activities including glutamatergic neurotransmission, the encoding of voltage-gated ion channels, synaptic plasticity, and the expression of the dopamine receptors. The dopamine receptors are the target sites for antipsychotic medications. Transcripts of the 108 genes also revealed elevated patterns of expression in the fetal brain as compared to the post-natal brain. Findings of similar studies have also shown increased expression of schizophrenia risk in the early stages of brain development. Findings from these studies align with a generalized neurodevelopmental role for most of the genes that are involved in the risk of schizophrenia. Further, studies have also reported the presence of various schizophrenia-associated loci which are rare in the disease population. For instance, in a meta-analytical study of 21,094 cases and 20,227 controls, the researchers identified copy number variants mapping to 8 Loci (Föcking et al., 2019). These loci included the NRXN1 the neurexin actively involved in the formation for synapse and the transmission process.

In a study investigating transcription-wide association together with descriptions of chromatin activity, gene splicing, and gene expression, the researchers found transcriptional changes in 157 genes. These transcriptional changes were directly linked to the risk of schizophrenia (Föcking et al., 2019). These changes were also strongly associated with nearby chromatin features, further supporting the significance of epigenetic mechanisms in the development of schizophrenia.

Studies have reported a loss of function mutation as a potential contributor to the risk of schizophrenia. Mutation of the gene encoding for histone H3 methyltransferase SETD1A, for instance, elevates the risk of this disorder. Acetylation and deacetylation of histone under the catalytic activity of histone deacetylases and acetyltransferases play an integral role in gene regulation (Thomas, 2017). This process involves the addition or the replacement of an acetyl group at the N-terminal of the histone molecule. Acetylated histones represent epigenetic markers in chromatin. Since acetylation eliminates the positive charge on the histone molecule, it decreases the interaction of the positively charged DNA phosphate groups with the N termini of the histones. Consequently, a more relaxed chromatin structure that possesses a higher level of gene transcription is produced (Thomas, 2017).

Evidence shows that there is a possibility of post-translational histone modifications in most psychotic conditions including schizophrenia. Post-translational histone modification is a potentially complex process that involves more than a hundred histone post-translational modifications (PTMs) that are residue-specific (Halene, Peter & Akbarian, 2014). A combination of different Histone PTMs makes up a histone code, which defines chromatin states including enhancers, promoters, repressor elements and gene bodies as well as other regulatory sequences.

Histone PTMs demonstrate a high level of coordination. This coordination is expressed in all body cells including the brain cells (Halene, Peter & Akbarian, 2014). Therefore, abnormalities in the PTMs may affect this coordination thus triggering the development of psychiatric symptoms. Post-translational histone modifications can induce either a repressive or facilitative state depending on the amino acid residue implicated. For instance, the methylation of the 4th lysine in H3K4 facilitates gene expression the methylation of the 9th lysine on H3K9of histone 3 produces a repressive effect (Gavin & Sharma, 2010).

Akbarian (2014) reported that significant hyperacetylation of Histone (H3K9K14), as well as enzymatic methylation of these proteins, was detected in persons presenting with schizophrenia. These findings suggest that gene expression changes exemplified in schizophrenia emanate from changes in epigenetic mechanisms involving acetylation and deacetylation of histone. Postmortem cohorts of schizophrenia brains revealed an elevated expression of Class 1 histone deacetylase (HDAC1) in the prefrontal cortex (Akbarian, 2014). This shows that abnormal expression of HDAC1 is a molecular pathology in the corticolimbic circuitry representative of schizophrenia. The deacetylation of Histone H3K9 and H3K27 represents some of the repressive epigenetic processes that affect gene expression. This process can occur through direct and indirect processes. Exposure to certain psychotic drugs may influence the Histone

PTMs coordination by acting on the dopamine D2 receptors (Halene, Peter & Akbarian, 2014).

This knowledge can be utilized to facilitate the development of effective psychotropic agents to treat severe psychiatric disorders.

DNA methylation is the other epigenetic process that impacts the expression of a gene.

Methylation is the process through which a methyl group is added to the DNA through covalent bonding. This epigenetic process constitutes some of the extensively studied chromatin modifications associated with the development of schizophrenia. Methylation occurs at cytosine residues but has also been reported at adenosine residues. Since the vertebrate genome is huge and complex, methylated DNA adds a layer of regulation for purposes of refining the cellular transcriptional profile (Christopher, Kyle & Katz, 2017). The methylation process occurs in the presence of the enzyme DNA Methyltransferase. The covalent binding of a methyl group to promoter regions has significant implications on transcription. For instance, it interferes with the binding of the transcriptional factors subsequently silencing the gene. This binding prevents the transcription of the code thus preventing gene expression. Post-mortem tissue of the brain from schizophrenia cases exemplify elevated levels of di- and tri-methylation of genes involved in the regulation of GAD1 expression. This implies that hyper-methylation subsequently reduces the expression of genes involved in neuronal metabolism. These changes were also noted in lymphocyte extracts from schizophrenia patients. These findings warrant further investigation as potential epigenetic markers of this disorder (Akbarian, 2014).

GABAergic interneurons are actively involved in the regulation of prefrontal glutamatergic neurons (Shorter & Miller, 2015). However, in schizophrenia, this signaling is dysregulated. Post-mortem analyses of schizophrenic brains reveal a reduction in the number of genes associated with the synthesis and signaling of GABA. Studies show that DNA Methylation results in the down-regulation of GABAergic genes in the hippocampal and cortical tissue samples of persons who died due to schizophrenia and its related complications. Normally, these proteins play an essential role in the transmission of signals to GABAergic neurons. Any abnormalities targeting these proteins results in the symptoms experienced by persons with schizophrenia (Lee & Huang, 2016). Shorter and Miller (2015) reported that polymorphisms in GABA-expressed genes lead to atypical GABAergic interneuron development subsequently leading to molecular and behavioral phenotypes similar to schizophrenia. These experimental findings indicate the presence of a strong connection between epigenetic changes and schizophrenia.

Methylation has also been shown to affect the expression of brain-derived neurotrophic factor (BDNF), a protein crucial for learning and cognition (Snyder & Gao, 2020). The findings by Snyder and Gao (2020) revealed that fear contributes to changes in the methylation levels in brain-derived neurotrophic factor promoter regions located in the hippocampal neurons. The researchers also reported that inhibition of DN-methyltransferase activity could alter the levels of BDNF in the hippocampus (Snyder & Gao, 2020). The environmental factors that affect the methylation of BDNF DNA include stress, post-natal social experiences, and deprivation of social interactions. These stimuli also contribute to an increase in the levels of anxiety, decreased cognition, and anti-social behaviors (Bathina & Das, 2015). All these factors point to the presence of a potential link between BDNF and schizophrenia.

Research findings

Research findings indicate that alterations related to DNA methylation are overly represented in persons with schizophrenia and other psychotic disorders. Shorter and Miller (2015), for instance, reported that many psychiatric disorders are typified by alterations in DNA methylation. It is, therefore, appropriate to hypothesize that methylation of DNA and other alterations associated with epigenetic mechanisms play a role in schizophrenia. Previous studies have suggested that epigenetic DNA modifications could explain the inconsistency witnessed in twin studies. Studies of monozygotic twins have, for instance, shown that differentially methylated regions are overly represented in psychotic disorders (Swathy & Banerjee, M. (2017). These findings are also supported by Lee and Huang (2016), who reported that brains from schizophrenia patients express an upregulation of DNA methyltransferases. The changes in these enzymes subsequently lead to hypermethylation and downregulation of genes associated with schizophrenia. These genes include reelin (RELN), GAD1, glucocorticoid receptor (NR3C1), and brain-derived neurotrophic factor (BDNF) (Di-Carlo, Punzi & Ursini, 2019).

Notably, as highlighted by Shorter and Miller (2015), the methylation of RELN promoter in temporal cortical tissue tends to increase during adolescence. This suggests that alterations in epigenetic regulation of this gene play a role in schizophrenia-related neurodevelopmental changes experienced during adolescence and early adulthood. Normally, the process of DNA methylation is catalyzed by DNA methyltransferases (DNMTs). The resultant component is a modified 5-methylcytosine (5-mC) that represses transcription near gene promoter regions. On the contrary, the TET enzyme catalyzes the DNA de-methylation process leading to transcriptional derepression. These facts are confirmed by evidence from Shorter and Miller (2015) who reported elevated levels of TET enzymes in corticolimbic tissue from schizophrenia brain postmortem.

Research findings have also revealed that acetylation of Histone at K14 and K9 plays a role in expression for 8 schizophrenia-related genes (Tang, Dean & Thomas, 2011). The researchers also reported that acetylation patterns at different loci revealed unique age and disease-related effects in normal subjects as well as those with schizophrenia.

Significance of Results

The information contained in this review can be utilized in various activities relating to treatment, prevention, and management of schizophrenia. This information can potentially help to increase understanding of the mode of action of antipsychotic medications and the modifications that are needed to achieve maximum response. For instance, Ovenden, McGregor, Emsley, and Warnich (2018) noted that response to antipsychotic medications in persons with schizophrenia is a complicated multifactorial trait that is influenced by numerous pharmacogenetic factors. Since only a few genetic studies offer comprehensive biological insight into this issue, the findings of this exercise will provide reliable information to address the missing hereditability of drug response in schizophrenia. Notably, scientists have started exploring the connection between epigenetic alterations and treatment outcomes. This has led to Histone acetylation and DNA Methylation, for instance, being some of the extensively studied epigenetic mechanisms in schizophrenia. These epigenetic alterations have been sufficiently explored in this exercise. Evidence supports the presence of a connection between epigenetic mechanisms and schizophrenia. Information from this investigation can help to resolve the mystery of why antipsychotic medications fail to achieve the anticipated response in most of the patients. Further, an understanding of the role of histone acetylation in the development of schizophrenia and other psychotic disorders has potentially important therapeutic implications, whereby the application of histone acetylase and histone deacetylase inhibitors may play a crucial role in the restoration of histone acetylation patterns and gene expression aimed at treating subjects with schizophrenia (Thomas, 2017).

Conclusion

Schizophrenia is a highly polygenic heritable disorder. Understandably, no single specific genes have been recognized as the sole contributor to the development of this disorder. However, phenotypic expressions of schizophrenia are attributable to complex interactions between environmental factors and genetic risk factors. Strong evidence has been presented revealing that pre-and postnatal environment factors can have a significant impact on promoter methylation of genes including those liked to psychotic disorders. Environmental factors such as reduced postnatal care can potentially alter specific and genome-wide gene methylation. Most of the DNA modifications that occur in the early stages of life are stable and capable of modifying neurobiology and adult behaviors. Epigenetic mechanisms, such as DNA methylation which is one of the extensively studied chromatin properties, and histone modifications may interact with parental imprinting and other genomic factors resulting in hypermethylation of parental copy of schizophrenia risk genes. Post-translational histone modifications lead to alteration of chromatin structure at the gene promoter regions in response to environmental factors consequently affecting the transcription of genes. Potential results include a decrease in histone acetylation which in turn elevates the heterochromatin levels in cortical tissue of the brain from schizophrenia patients. This indicates that alterations in histone acetylation can potentially contribute to the development of schizophrenia.

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