The Role of Epigenetics in Psychosis

*Esmaeil Shahsavand Ananloo*

#### **Abstract**

Epigenetics (genome - environment interaction) is the study of mitotically heritable, but reversible changes in gene expression without any change in DNA modifications and the chromatin structure. Transition to psychosis is a complex and longitudinal process during which epigenetic changes have been hypothesized and investigated. This process is especially important in individuals at high/ultrahigh risk for psychosis, before the development of full-blown psychosis. Psychoses is a range of complex disorders, where genetic variants explain only a portion of risk. Neuro-epigenetic mechanisms may explain the remaining share of risk, as well as the transition from susceptibility to the actual disease. There is a need for computational model of psychosis integrating genetic risk with environmental factors (epigenetic) associated with the disorder to discover its pathophysiological pathways. Epigenetic dysregulation of many genes has been widely speculated that are important factors involved in etiology, pathophysiology, and course of the psychoses, such as schizophrenia, and mood disorders with psychotic features. In addition, the role of epigenetic changes, including histone and DNA modifications and also targeting microRNAs in the treatment of psychoses is a new field of investigations.

**Keywords:** psychosis, epigenetic, etiology, pathophysiology

#### **1. Introduction**

Epigenetic mechanisms, link between the environment and the genome, are known to play a major role in the structure and also physiology of the human central nervous system (CNS), such as learning, memory, circadian clock and neural plasticity [1–4]. During the last decade, a huge amount of investigations in multi-omics era, including genomics, transcriptomics, proteomics, metabolomics, lipidomics, microbiomics, epigenomics, interactomics, and connectomics have pushed brain development into the "big data" era [5–10]. Multi-directional differentiation ability and self-renewal are two primary properties that characterize embryonic stem cells [11, 12]. The major cell types in the CNS, including neurons, astrocytes, and oligodendrocytes are generated from common neural stem cells (NSC) [13, 14]. There is a large number of interdependent factors, such as epigenetic modifications, pro-inflammatory cytokines, intracellular signaling pathways, and protein complexes play important role in regulating the differentiation potential and fate specification of NSC [11, 15–17]. It is known that the epigenetic mechanisms play an important role, not only in neurogenesis during the periods of fetal life and childhood, but also in neurogenesis takes place during adulthood in the mammalian brain [18].

Recent studies highlighted that microRNAs (miRNAs) as a type of epigenetic modifications, have the pivotal role in balancing the switch from self-renewal to differentiation of embryonic stem cells (ESCs) [19]. Evidence has shown that specific circular RNA (circRNA) expression patterns are significantly associated with adult stem cell self-renewal and differentiation [17]. Epitranscriptomics (chemical modifications on RNA), including N6-methyladenosine (m6 A), 2-O-dimethyladenosine (m6 Am), N1-methyladenosine (m1 A), 5-methylcytosine (m<sup>5</sup> C), and isomerization of uracil to pseudouridine (Ψ) has recently garnered attention, and has biological consequences, such as embryonic stem cell differentiation, brain development, and neurodevelopmental disorders [20, 21].

In the field of mental disorders, epigenetic mechanisms are thought to play a major role in the pathogenesis of the psychoses, including schizophrenia (SCZ) and bipolar disorder (BD) [22–24].

In this review article, after a brief introduction, I will discuss around: 1) the concept of epigenetics, including its definition and applications, 2) epigenetics and psychosis, including an overview of psychosis, and short references to the roles of genetics, environment, and epigenetics in psychosis, 3) the epigenetics findings in psychosis, including a dynamic approach to psychosis, epigenetic findings in prodromal phase of psychosis, in first-episode psychosis, in overt psychosis, and in methamphetamine-induced psychosis.

#### **2. The concept of epigenetics**

#### **2.1 Definition**

In as early as 1942, Conrad Waddington (as an embryologist) first defined the field. Epigenetics means "above" or "on top of" genetics. Epigenetics is the study of mitotically heritable, but reversible, changes in gene expression that occur without a change in the genomic DNA or histone sequences, principally through modifications in chromatin structure, including DNA and histone. Epigenetics is the study of how our behaviors and environment can cause changes that affect the way our genes work.

The epigenome is a dynamic concept, and refers to the biological mechanisms, which regulate gene expression (such as DNA methylation). Although the epigenome can be altered by environmental factors, but it is stable overall [25].

#### **2.2 Epigenetic mechanisms**

These mechanisms are necessary for the regulation of gene expression and chromatin architecture at a genome-wide level in mammalian, including human cells, and play critical roles in both normal human development and disorders. Epigenetic modifications are tissue specific. There are several known mechanisms for epigenetic modification. These mechanisms are DNA and histone posttranslational modifications, including methylation, acetylation, phosphorylation, and ubiquitination, and also non-coding RNAs regulation. The methylation of DNA cytosine residues at the carbon 5 position is a common epigenetic modification that is often found in the sequence context CpG [26].

#### **2.3 Epigenetic applications**

Interest in the field of epigenetics, as well as the usage of the term, have increased significantly over the last few years [27]. Up to the January of 2021,

#### *The Role of Epigenetics in Psychosis DOI: http://dx.doi.org/10.5772/intechopen.99231*

there are 102,898 citations (29,879 reviews, 424 systematic reviews, 328 metaanalyses, and 72,267 other types of articles, including original articles) related to "epigenetics" in PubMed. In 2004, however, this number was 1017 (85 article every month), and rose to 13,125 in 2020 (1094 article every month; ~ 13 times more). In addition, there are 1,016 citations (116 reviews, 26 systematic reviews, 39 metaanalyses, and 835 other types of articles, including original articles) related to "epigenome-wide association study".

The concept of epigenetic has spread into different fields, that do not address just the genetics, such as neuroscience [28, 29], physiology [30, 31], psychiatry [32–34], addiction [35], stress [36–38], and aging [39, 40].

Complex disorders, such as endocrine, cardiovascular, skin, autoimmune, or mental disorders, result from complex interactions between genes and the environment. For example, increased DNA methylation variability may be involved in obesity [41], ischemic heart disease [42], or major depression disorder [43, 44]. Regarding the psychosis, there are 294 citations (118 reviews, 5 systematic reviews, 2 meta-analyses, and 169 other types of articles, including original articles) related to "epigenetic and psychosis", and 1058 citations (416 reviews, 13 systematic reviews, 7 meta-analyses, and 622 other types of articles, including original articles) related to "epigenetic and schizophrenia" in PubMed (accessed on January 2021).

#### **3. Epigenetics and psychosis**

#### **3.1 An overview to psychosis**

Psychotic disorders are among the frequent and disabling human disorders. In recent years, the concept of psychosis has moved from just a chronic disorder to a more dynamic paradigm. Psychosis is now conceptualized as a progressive mental disorder with transitions across several stages: early vulnerability, at-risk or ultra-high risk (UHR) mental state, first episode, and chronic disorder [25]. Schizophrenia and BD are chronic mental disorders, both considered as "major psychosis"; they are thought to share some pathogenetic factors involving dysfunctional gene x environment interactions [45]. They have heterogeneous psychiatric phenotypes, and their etiology and physiopathology still remain largely unknown [24, 46]. Psychotic disorders are highly heritable, and have polygenic inheritance underlain by pleiotropic genes [34]. So, both the genetic and environmental factors are involved in the etiology and course of the major psychoses, such as major depressive disorder (MDD), BD, and SCZ [47, 48].

#### **3.2 An overview to the role of genetics in psychosis**

Although some progress has been made in the understanding of genetic physiopathology of psychoses, and despite success in identifying cytogenetic deletions or insertions, and also genetic variants and polymorphisms associated with them, it seems that the molecular genetic findings could not yet to elucidate the exact molecular pathogenesis of different forms of psychoses [49]. Many candidate genes have been identified showing a very high genetic heterogeneity of psychoses. These genes are overrepresented in synaptic and neurotransmission pathways. Different types of common and rare genetic variants, including single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) with small or large effects have also been identified in the last years. The genetic variations may impact on local DNA methylation patterns [50]. All of these findings are important in clinical

practice as they can lead to therapeutic challenge or genetic counseling, but only a small fraction of psychosis could be easily explained by genetics [24].

#### **3.3 An overview to the role of environmental factors in psychosis**

Regarding the role of environmental factors in psychosis, many stressful life events, including obstetric complications, mother tobacco use during the pregnancy, and her physical inactivity, childhood trauma, emotional abuse, physical neglect, heightened sensitivity to stressful events, childhood and adolescent low functioning, affective comorbidities, male gender, single status, unemployment and low educational level have been reported [23, 51]. Trauma during the childhood mediates the epigenome and gene expression profile, and could provide a mechanism underling psychosis [22].

#### **3.4 An overview to the role of epigenetics in psychosis**

A large amount of epigenetic research in mental health was performed during the last decade. The results of these efforts have "revolutionary" potentials for the development of new interdisciplinary models of mental health [52]. Evidence show that the risk factors for psychosis were not solely due to the DNA sequence, but also abnormal epigenetic modifications have important role in the etiopathology of these disorders [53]. It has been widely speculated that a wide range of epigenetic modifications of the genome, such as DNA methylation, post-translational histone modifications (in particular the histone 3 lysine 4; H3L4), and non-coding RNAs (such as miRNAs) may mediate gene–environment interactions at the molecular level, and through transcription factors modulate the expression of psychiatric phenotypes, including the variability in symptom severity and family heritability [34, 46].

Several studies have investigated the epigenetic pattern, including DNA methylation pattern in patients with major psychosis in different tissues and associated this epigenetic modification with psychiatric phenotype [54–57]. The main hypothesis for the development of psychotic disorders, proposes that a combination of genetic and environmental factors, during critical periods of brain development, including prenatal and postnatal periods increase the risk for these disorders [46]. The epigenetic mechanisms are important heritable and dynamic means of regulating various genomic functions, including gene expression. These mechanisms orchestrate brain development, adult neurogenesis, and synaptic plasticity. These processes when perturbed are thought to contribute to psychosis, such as SCZ pathophysiology [58]. However, new epigenetic technologies may be able to uncover etiopathogenic mechanisms of major psychosis [59]. For example, There are significant differences were detected in both CpG and CpH modifications between patients with SCZ and healthy controls [59].

#### **4. The epigenetics findings in psychosis**

#### **4.1 Epigenetics findings in prodromal phase of psychosis**

The research about the complex interactions between the stressful life events with dysregulation of biological stress response systems (such as hypothalamic– pituitary–adrenal [HPA] axis) and genes; epigenetic changes; in one hand, and the initial emergence of psychosis, on the other hand, has increasingly focused on the prodromal phase of psychosis, the period of functional decline that precedes clinical illness [51]. In comparison with general population, childhood adversity

#### *The Role of Epigenetics in Psychosis DOI: http://dx.doi.org/10.5772/intechopen.99231*

rates would be higher in people at UHR of psychosis [60]. Several models, such as dysfunctional cognitive patterns, and epigenetic dysregulation have been cited to explain the link between trauma and the subsequent onset of psychosis [60].

It has been estimated that around 30 to 40% of UHR individuals convert to fullblown psychosis in the following 24 to 36 months [61]. Conversion to psychosis, especially in high and/or UHR individuals is a longitudinal process during which several epigenetic changes have been described [25]. As a few examples, it has been reported that conversion to psychosis is associated with specific methylation changes in two regions, including 1q21.1 and a cluster of six CpG regions located in glutathione s-transferase mu 5 (*GSTM5*) gene (chr1p13.3) promoter [62]. Bang et al. [63] suggest that epigenetic alterations of oxytocin receptor (*OXTR*) gene, located on chromosome 3 (chr3p25.3) can be detected before the development of full-blown psychosis (**Table 1**).


**Table 1.**

*An overview to the epigenetic studies in prodromal phase of psychosis.*

#### **4.2 Epigenetics findings in first-episode psychosis**

The onset of psychosis is the result of complex interactions between genetic vulnerability to psychosis and response to environmental and/or developmental changes. Epigenetic modifications mediate the interplay between genes and environment leading to the onset of psychosis [62]. It has been hypothesized that the neural diathesis-stress model proposes that different stressors act on a pre-existing vulnerability and thus triggers the presenting symptoms of psychosis [64].

The global DNA hypomethylation; increased methylation and reduced gene expression of GTP cyclohydrolase 1 (*GCH1*, located on chromosome 14 [chr14q22.2]), hyperexpression of udE neurodevelopmental protein 1 like 1 (*NDEL1*, located on chromosome 17 [chr17p13.1]), AKT serine/threonine kinase 1 (*AKT1*, located on chromosome 14 [chr14q32.33]), DICER1 antisense RNA1 (*DICER1*, located on chromosome 14 [chr14q32.13]), and hypoexpression of drosha ribonuclease III (*DROSHA*, located on chromosome 5 [chr5p13.3]), catechol-Omethyltransferase (*COMT*, located on chromosome 22 [chr22q11.21]), and disturbed in schizophrenia 1 (*DISC1*, located on chromosome 1 [chr1q42.2]) have all been reported in first-episode psychosis [22].

Hypomethylation has been founded among all CpGs analyzed within the promoter of glutamate ionotropic receptor NMDA type subunit 2B (*GRIN2B*) gene, located on chromosome 12 (chr12p13.1) in patients with first-episode patients with SCZ and greater LINE-1 type transposase domain-containing protein 1 (*L1TD1P1*) gene, located on chromosome 1 (chr1p31.3) methylation in patients and their siblings [65].

Human endogenous retroviruses (HERV) have been widely associated with the etiology of SCZ. The lower endogenous retroviral sequence K 2 (*ERVK2*, located on chromosome 19 [chr19q11]) methylation levels have been reported at early stages of SCZ [66].

#### *Psychosis - Phenomenology, Psychopathology and Pathophysiology*


**Table 2.**

*An overview to the epigenetic studies in first episode psychosis.*

Working memory and executive functions impairments emerge in first-episode psychosis, and even prior to its onset. It has been reported that NMDA receptor hypofunction is a feature of early postnatal development, with epigenetic hyperrepression of the glutamate ionotropic receptor NMDA type subunit 2B (*GRIN2B*), located on chromosome 12 (chr12p13.1) promoter being a contributing factor. This loss of NR2B protein may induce synaptic dysfunctions during development and may underlie early cognitive impairments in patients with SCZ (**Table 2**) [67].

#### **4.3 Epigenetics findings in overt psychosis**

Although numerous studies have examined psychosis-associated gene expression changes, epigenetic studies of psychosis are in their infancy [55]. For example, it seems that DNA methylation plays an important role in SCZ; directly as a mechanism of pathogenesis or as a risk biomarker [68]. Different epigenetic modifications have been reported in psychosis, genes implicated in dopaminergic, serotonergic, GABAergic and glutamatergic pathways [45, 46]. Specific changes in promoter DNA methylation activity of genes related to SCZ such as reelin, BDNF and GAD67, and altered expression and function of mGlu2/3 receptors in the frontal cortex have been reported [45].

Abnormal neuronal processes, including dopamine imbalance, may be the central to the pathogenesis of major psychosis. DNA methylation, transcriptomic, and genetic-epigenetic interactions in major psychosis converged on pathways of neurodevelopment, synaptic activity, and immune functions [69]. It has been suggested that hypomethylation of the enhancer at insulin-like growth factor 2 (*IGF2*, located on chromosome 11 [chr11p15.5]) may enhance dopamine synthesis associated with major psychosis. This enhancer targets the nearby tyrosine hydroxylase (*TH*, located on chromosome 11 [chr11p15.5]) responsible for dopamine synthesis [69].

#### *The Role of Epigenetics in Psychosis DOI: http://dx.doi.org/10.5772/intechopen.99231*

Walton et al. [70] suggest that epigenetic alterations (DNA methylation) in genes implicated in neurodevelopment (such as Sp6 transcription factor; [*SP6*] gene, located on chromosome 17 [chr17q21.32]) may contribute to a brain-based biomarker (amygdala/hippocampal volume ratio) of psychotic psychopathology.

Reelin (RELN) is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions [71]. Reelin located on chromosome 7 (chr7q22.1) is one of the most frequently studied candidates in methylation studies of SCZ [26]. Reelin is mostly synthesized in GABAergic neurons of corticolimbic structures. Reelin binds to AUP1 lipid droplet regulating VLDL assembly factor (*AUP1*, located on chromosome 2 [chr2p13.1]), apolipoprotein E (*APOE*, located on chromosome 19 [chr19q13.32]), and α3β2 Integrin receptors located on dendritic shafts and spines of postsynaptic pyramidal neurons. It has been shown that altered *RELN* expression in patients with SCZ and BD patients is associated with altered epigenetic homeostasis [72].

The loss of the human brain regions laterality (such as in temporal lobe, basal ganglia and white matter microstructure) is one of the most consistent modalities in SCZ and BD [73–75]. This loss of brain laterality corresponds to aberrant epigenetic regulation of transforming growth factor beta 2 (*TGFB2*, located on chromosome 1 [chr1q41]) and changes in transforming growth factor beta superfamily (TGFβ) signaling [76]. These findings may be potential avenues for disorders prevention/ treatment.

In their metagenome-wide association study (MWAS), Aberg et al. [26] found that MINDY2 lysine 48 deubiquitinase 2 (*MINDY2*, located on chromosome 15 [chr15q21.3-q22.1]), a part of the networks regulated by microRNA (as an epigenetic regulator), is linked to neuronal differentiation and dopaminergic gene expression [77–79], that has potential relevance to SCZ.

Epigenetic alterations of oxytocin receptor (*OXTR*) gene, (located on chromosome 3 [chr3p25.3]) occur across psychotic disorders. It has been reported that patients with SCZ (especially in women) show higher levels of DNA methylation. This pattern of *OXTR* methylation is associated with poorer emotion recognition, smaller volumes in temporal-limbic and prefrontal regions [80].

Discoidin domain receptor 1 (*DDR1*) gene is located on chromosome 6 (chr6p21.33). *DDR1* hypermethylation has been found in patients with psychosis. This hypermethylation is associated with mental stress, and neutrophil-to-lymphocyte ratios [81].

The brain parvalbumin deficits are a consistent finding in SCZ and models of psychosis. Greater methylation of parvalbumin (*PVALB*) gene, located on chromosome 22 (chr22q12.3) is found in hippocampus of the patients with SCZ. The LINE-1 type transposase domain-containing protein 1 (*L1TD1P1*) gene methylation, as a measure of global methylation, is also elevated in both regions of hippocampus and prefrontal cortex in SCZ [82].

Associations between altered DNA methylation of the serotonin transporterencoding gene (*SLC6A4*, located on chromosome 17 [chr17q11.2]), and early life events, and mood disorders have been reported. Childhood trauma exposure may be a robust environmental risk factor for psychosis. However, not all exposed individuals develop psychotic symptoms later in life [83]. Hypermethylation of the CpG site in *SLC6A4* is involved in the pathophysiology of SCZ, especially in male patients harboring low-activity 5-HTTLPR alleles [84].

Histone deacetylases (HDACs) are enzymes that regulate cognitive circuitry. HDAC expression positively correlate with cognitive performance scores [85]. Postmortem brain studies support dysregulated expression of the histone deacetylase enzymes, HDAC1 and HDAC2, as a central feature in disorders, including SCZ

#### *Psychosis - Phenomenology, Psychopathology and Pathophysiology*


#### **Table 3.**

*An overview to the epigenetic studies in overt psychosis.*

and BD [86]. It has been reported that HDAC expression is lower in the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal gyrus, and higher relative HDAC expression in the cerebral white matter, pons, and cerebellum of patients with SCZ (**Table 3**) [85].

In utero exposure to diethylstilbestrol (DES), psychosis is associated with specific methylomic modifications that could impact neurodevelopment and neuroplasticity [87].

It seems that the neuronal synapses are fundamental units of mental activities. Despite the diverse origins of specific molecular dysfunctions of mental disorders, disruption of synaptic regulation, which is fundamental to behavioral adaptation to the environment, is so important. A novel class of molecular regulators of fine synaptic tuning known as long non-coding RNA (lncRNA) operates as epigenetic modifiers and enhancers of proteome diversity [88]. Non-coding RNAs, including specific microRNAs and lncRNAs provide a novel and complex mechanism of gene regulation [89]. Evidence shows remarkable alterations of the expression of lncRNAs in mental disorders, such as SCZ, suggesting the disruption of fine synaptic tuning underlying psychosis [88].

#### **4.4 Epigenetics findings in methamphetamine-induced psychosis**

Methamphetamine (MAP) causes severe substance dependence and psychosis, similar to SCZ, through the alterations in gene expression [90]. Evidence shows that epigenetic factors may play important role in methamphetamine psychosis. Nohesara et al. [91] found statistically significant DNA hypomethylation of the promoter regions of dopamine receptor D3 (*DRD3*, located on chromosome 3 [chr3q13.31]), dopamine receptor D4 (*DRD4*, located on chromosome 11 [chr11p15.5]), *MB-COMT*, and *AKT1* associated with increased expression of the corresponding genes in patients with methamphetamine psychosis. It is suggested


**Table 4.**

*An overview to the epigenetic studies in methamphetamine-induced psychosis.*

that MAP can alter DNA methylation of *RELN* and tRNA aspartic acid methyltransferase 1 (*TRDMT1*, located on chromosome 10 [chr10p13]) genes in hippocampus dentate gyrus, and decrease in *RELN* mRNA in the frontal cortex. These alterations might be related to SCZ-like psychotic symptoms of MAP psychosis (**Table 4**) [90].

#### **5. Summary and future directions**

#### **5.1 Summary**

In this review article, after a brief introduction, I discussed the concepts of psychosis and epigenetics, and also references to the roles of genetics, environment, and epigenetics in psychosis. In addition, I mentioned the epigenetics findings in prodromal phase of psychosis, first-episode psychosis, overt psychosis, and also in methamphetamine-induced psychosis.

Psychotic disorders, such as SCZ and BD are among the frequent, disabling, progressive, and chronic human mental disorders, and have heterogeneous psychiatric phenotypes. Psychosis has several stages, including early vulnerability, at-risk or ultra-high risk mental state, first episode, and chronic disorder. It seems that dysfunctional genes x environment interactions influence their pathogenesis. Psychotic disorders are highly heritable, and have a polygenic inheritance pattern. Despite success in identifying cytogenetic changes, many candidate genes in synaptic and neurotransmission pathways, and also genetic polymorphisms, including SNPs and CNVs associated with psychosis, the molecular genetic findings could not yet explain its exact molecular pathogenesis. Although all of these findings are important in clinical practice, such as therapeutic challenge or genetic counseling, but only a small fraction of psychosis could be easily explained by genetics. However, the genetic variants explain only a portion of risk, and the epigenetic mechanisms may explain the remaining share of risk. In addition, many stressful environmental factors, such as obstetric complications, childhood trauma, different forms of child abuse or neglect have also been reported to play roles in the association with psychosis. These factors mediate the epigenetic modifications, and could provide a mechanism underling psychosis.

Epigenetics means "above" or "on top of" genetics. It refers to the biological mechanisms, which regulate gene expression. Epigenetics is the study of reversible changes in gene expression without any change in chromatin structure. The DNA methylation of cytosine residues at the carbon 5 position is a common epigenetic modification. Interest in the field of epigenetics has increased significantly over the last few years. It plays a key role in the structure and also physiology of the

human CNS, and also in the development of complex disorders, such as endocrine, cardiovascular, skin, autoimmune, and mental disorders. Epigenetic mechanisms, including DNA and histone modifications, and also non-coding RNAs are especially important mechanisms to detect the people with high/ultrahigh risk for psychosis.

A large amount of epigenetic research in mental health was performed during the last years, and these efforts have "revolutionary" potentials for the development of new interdisciplinary models of mental health. The main hypothesis for the development of psychotic disorders, proposes that a combination of genetic, environmental, and developmental factors increase the risk for these disorders. It has been widely speculated that a wide range of epigenetic modifications of the genome may mediate gene–environment interactions and modulate the expression of psychiatric phenotypes. There are some epigenetic dysregulations in prodromal phase of psychosis, to find the people at UHR of psychosis. During the conversion to psychosis, especially in high and/or UHR individuals, several epigenetic changes have also been described. Epigenetics findings in first-episode psychosis shows that the epigenetic modifications of many genes lead to the onset of psychosis. In addition, numerous studies have examined many psychosis-associated gene expression changes in overt psychosis, including methamphetamine-induced psychosis. For example, several epigenetic modifications in genes implicated in dopaminergic, serotonergic, GABAergic and glutamatergic pathways, have been reported in psychosis.

#### **5.2 Future directions**

Attempting to predict future is so difficult. This is particularly true in the field of psychiatry. This in mainly due to essential deficiencies in understanding the etiopathogenesis of mental disorders. For example, mapping the relationship between human epigenetics and mental and psychiatric phenotypes is a challenging task. It is essential to shift paradigm in understanding the etiology and pathophysiology of different forms of psychosis.

During the last years, a large amount of studies in multi-omics era have pushed brain development into the "big data" era, and may promise to answer major questions of psychiatry [92]. Nowadays, there are available web-based tools for integration and interpretation of omics data. Although a large amount of studies has been performed and significant progress has been made in past years, different factors, including the high heritability, clinical heterogeneity (etiological and symptomatological), and genetic and epigenetic heterogeneity of psychosis still post as major challenges to the epigenetic dissection of this complex syndrome. However, understanding of epigenetic mechanisms is important to understand the pathogenic pathways in complex disorders, including psychosis [93]. The epigenetic studies could represent a promising approach to better understanding and treating mental disorders. The methylation modifications may be used as diagnostic markers of disorder phenotype and predict the progression and response to treatment. So, the targeted epigenetic pharmacotherapy, in combination with other types of effective interventions, will be effective for future personalized psychiatry for patients [94].

Despite significant progress in identifying the mechanisms underlying psychosis, there are no valid biomarkers for both disorder phenotyping and treatment response. It seems that psychiatric diagnosis based on biomarkers will be more valid and reliable than symptoms-based diagnosis. The discovery of biomarkers, such as epigenetic biomarkers in mental disorders will help in the prevention, diagnosis, and treatment of patients with these disorders [95]. DNA methylation may play an important role in psychosis as a biomarker of risk. Blood DNA-methylation signatures show promise of serving as a biomarker of SCZ [96]. However, the sensitivity

#### *The Role of Epigenetics in Psychosis DOI: http://dx.doi.org/10.5772/intechopen.99231*

and stability of epigenetic alterations in specific genes make them promising candidates for robust biomarkers [94, 97].

Finally, there is a need for computational model of psychosis integrating genetic risk with environmental, and developmental factors associated with the disorder to discover its pathophysiological pathways, and more accurate treatment targets for psychosis. Hopefully, the epigenetics may provide new insights into a more comprehensive interpretation of mental disorders, such as psychosis and might eventually improve the nosology, treatment, and prevention of these complex disorders.

## **Author details**

Esmaeil Shahsavand Ananloo Department of Psychosomatic, Imam Khomeini Hospital Complex (IKHC), School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran

\*Address all correspondence to: shahsavand@tums.ac.ir; esmaeilshahsavand@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 7**

## DNA Methyltransferases and Schizophrenia: Current Status

*Pranay Amruth Maroju and Kommu Naga Mohan*

#### **Abstract**

Schizophrenia (SZ) is a complex disorder without a single cause but with multiple etiologies. Monozygotic twin studies suggesting high discordant rates provide evidence for epigenetic mechanisms among the factors that result in increased susceptibility. Among the different epigenetic modifications in mammals, DNA methylation mediated by DNA methyltransferases (DNMTs) is the most-well studied. Studies on post-mortem brain samples and blood samples of SZ patients revealed altered levels of most DNMTs. In addition, some recent studies also reported disease-associated SNPs in the DNMT genes. While the effects of dysregulation of DNMTs are beginning to be understood, many unanswered questions remain. Here, we review the current evidences that shed light on the relationship between DNMT dysregulation and SZ, and suggest the possible strategies to address some of the unanswered questions.

**Keywords:** Schizophrenia, DNA methyltransferases, DNA methylation, Dysregulation, Abnormal neurogenesis

#### **1. Introduction**

Schizophrenia (SZ) is a severe and chronic mental disorder with an incidence of 1%, affecting 20 million people worldwide [1]. The main symptoms of SZ include hallucination, delusion, abnormal disorganized behavior, disorganized speech, disturbances of emotions such as marked apathy, etc. The disorder is associated with considerable disability and can affect educational and occupational performance with 2–3 times increased likelihood of death earlier than the general population [2].

SZ is a complex disorder with no single causative factor but with multiple etiologies (**Table 1**). The five main factors that are believed to result in increased risk are: physical and chemical changes in brain [3], pregnancy or birth complications [4], childhood trauma [5], genetic [6] -and epigenetic [8]. Among these, a high risk among first-degree relatives compared to the general population and increased risk in monozygotic than dizygotic twins suggest genetic factors [7]. However, the observed concordance rates (50%) in monozygotic twins that were much lesser than expected for a purely genetic risk (nearly 100%) suggest the contribution of epigenetic mechanisms to SZ [9].

Recent data based on brain imaging and molecular-genetic studies suggest that SZ is a form of neurodevelopmental disorder [10]. The neurodevelopmental hypothesis for SZ suggests pathological neurodevelopment during first and second


#### **Table 1.**

*Risk factors for schizophrenia.*

trimesters of pregnancy results in altered neuronal circuits which in turn result in psychosis in adolescents or young adults when exposed to increased biological or psychological stress. Evidences in support of this hypothesis comes from genetic studies that identified affected genes and risk factors during perinatal life that may disrupt the normal process of neurodevelopment. In addition, studies over the past 20 years showed that in comparison with controls, SZ patients after the onset exhibit accelerated aging-related loss of brain tissue [11]. Specifically, the patients show increased age-related reduction in the proportion of grey matter compared with controls [12]. These findings suggest that altered neurodevelopment may underlie the processes associated with SZ.

#### **2. Epigenetic mechanisms**

As mentioned above, evidence on the contribution of epigenetic mechanisms in SZ comes from monozygotic twin studies wherein the concordance rates are only 50%. This low concordance rate suggests the interplay of genes and environment resulting in SZ. Because of this interplay, the epigenetic mechanisms have been suggested to be among the etiological factors [8]. Epigenetic mechanisms are defined as processes that can alter the patterns of gene expression without causing a change in the DNA sequence [13]. These mechanisms operate at the levels of transcription, mRNA stability and translation (**Table 2**). At the level of transcription, mammalian genes can be regulated by covalent modifications of the DNA [19], modifications of N-terminal tails of histones [15], microRNAs [20], circular RNAs [17] and long noncoding RNAs [21]. A number of modifications of RNA have been reported to influence mRNA stability and efficiency of translation. These modifications and their roles are described elsewhere [22, 23]. Because of epigenetic differences, genetically identical cells in a multicellular organism express different sets of genes that confer cell type – specific identity and function [24]. The most well studied epigenetic modification is methylation of the 5th carbon in the cytosine residues in the genomic DNA, often referred to as cytosine methylation. This modification mostly occurs in the CpG dinucleotides because of the maintenance mechanism in a post-replicative manner involving hemi-methylated DNA [see below]. As such, DNA methylation is often used as a synonym to CpG methylation


#### **Table 2.**

*Epigenetic mechanisms in regulating gene expression.*

in mammals. A family of enzymes, referred to as DNA methyltransferases (DNMTs) are responsible for establishment and maintenance of DNA methylation [25]. Several studies that focused on the relationship between DNA methylation and gene expression showed an inverse correlation, meaning that DNA methylation is

often associated with repressed state of the promoters [26]. In case of histones, the lysines in the N-terminal tails of core histones can either be acetylated or methylated. These modifications occur on the same lysine residues and are therefore mutually exclusive [27]. Whereas histone lysine acetylation is always associated with gene expression, histone methylation is associated with either expression or silencing depending on the residues involved [28]. For example, methylation at lysine 9 of histone H3 (H3-K9) or H3-K27 is associated with silencing. On the other hand, H3-K4 or H3-K36 methylation is associated with gene expression. Histone methyltransferases and histone acetyltransferases are two families of enzymes for imparting the two covalent modifications of the N-terminal tails of the core histones [29]. As in case of DNA methylation, histone marks are also heritable. The covalently modified nucleosomes from the parental chromatin are segregated equally among the two daughter DNA molecules so that additional nucleosomes containing histone marks identical to the parental nucleosomes are assembled [30]. Both DNA methylation and histone modifications are reversible involving different categories of enzymes and processes. The machinery of DNA methylation and demethylation is described in the next section [Section 2.1]. With regard to the histone modifications, histone demethylases (HDMs), histone methyltransferases (HMTs), histone acetyltransferases (HATs) and histone deacetylases (HDACs) together play a role in erasure and establishment of histone modification marks [31]. HDMs remove methyl groups from the lysines of the core histones so that the unmethylated lysines can be acetylated by HATs. HDACs, on the other hand, remove acetyl groups from the acetylated lysines so that the same residues can be methylated by HMTs.

Apart from covalent modifications of the genome, long noncoding RNAs (lnc RNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) also play an important role in regulating gene expression. Of these, circRNAs and miRNAs regulate expression at post-transcriptional levels whereas lncRNAs can regulate at both transcriptional and post-transcriptional levels. Lnc RNAs are ≥200 nucleotides, do not encode any protein and regulate genes at the both transcriptional and posttranscriptional levels [32]. At the level of transcription, lncRNAs either can promote histone modifications and chromatin condensation or recruit transcription factors to facilitate gene expression or evict transcription factors and result in gene repression. In addition, lncRNAs are also known to influence alternative splicing, polysome recruitment to enable translation, act as decoys for microRNAs (miRNAs) and regulate mRNA stability. The miRNAs, on the other hand cause translational repression of the target mRNAs. Each miRNA is �22 bases long and can recognize multiple targets having a few mismatches at their 3<sup>0</sup> -ends [33]. In cases, where there is no mismatch, miRNA can induce degradation of the target mRNA sequence [34]. CircRNAs are generated by back-splicing or non-colinear splicing of pre-mRNA molecules and may include both exonic and intronic sequences [35]. In addition to competing with canonical splicing and controlling the levels of the corresponding protein-coding mRNAs, circRNAs can also act as protein decoys or miRNA sponges to regulate gene expression [36].

#### **2.1 DNA methylation and demethylation machinery**

Of the different epigenetic mechanisms influencing gene expression described above, DNA methylation-mediated regulation of gene expression is the most-well studied. DNA methylation is established and maintained by DNMT family of enzymes whereas different mechanisms exist for demethylation (**Figure 1A**). Of the four members of DNMTs that facilitate DNA methylation, DNMT3L does not have an active methyltransferase (catalytic) domain. DNMT3A and 3B are *de novo* methyltransferases of which DNMT3A is mainly responsible for establishment of

*DNA Methyltransferases and Schizophrenia: Current Status DOI: http://dx.doi.org/10.5772/intechopen.98567*

#### **Figure 1.**

*DNA methylation and demethylation machinery. (A) Domains of DNMTs. CXXC: Cys-X-X-Cys domain, BAH: Bromo-Adjacent Homology domain, MTase: Methyltransferase domain, PWWP: Pro-Trp-Trp-Pro domain, ADD: ATRX-DNMT3-DNMT3L domain (B) Cytosines are methylated by* de novo *methyltransferases DNMT3A and DNMT3B with the help of DNMT3L. Only methylated CpGs are maintained by DNMT1. (C) Different pathways of demethylation of methylated cytosines (5mC). TET: teneleven translocation (TET) proteins, AID/APOBEC: activity-induced cytidine deaminase/ apolipoprotein B mRNA editing complex,Thy: thymine. TDG: Thymine-DNA glycosylase, AP: apurinic/apyrimidinic site, BER: base-excision repair. 5hmU: 5-hydroxymethyluracil, 5hmC: 5-hydroxymethylcytosine, 5fC: 5-formylcytosine and 5caC: 5-carboxylcytosine.*

methylation in imprinted genes whereas DNMT3B establishes methylation in pericentric repetitive regions [37]. DNMT1 is a maintenance methyltransferase, which methylates the daughter DNA strand in the hemi-methylated DNA generated after replication (**Figure 1B**). In this process, the methylated CpG sites in the parental strands serve as information to methylate the complementary CpG sites in the daughter strand. Demethylation, on the other hand can be achieved by cytidine deaminases or Ten-Eleven Translocation (TET) enzymes [38] (**Figure 1C**). Cytidine deaminases such as activated induced cytidine deaminase (AID) and apolipoprotein B mRNA editing enzyme catalytic polypetide 1 (APOBEC1) catalyze the conversion of methylcytosine to thymine [39], leading to T:G mismatches. These mismatches are repaired by base excision repair machinery that incorporates unmodified cytosine. The TET enzymes hydroxymethylate the methylated cytosines which are further processed into oxidized forms of cytosine (5-formylcytosine and 5-carboxycytosine) that are further subjected to base excision repair resulting

in active demethylation. Hydroxymethylcytosine results in passive demethylation via DNA replication because of absence of methylgroup in the parental strand in the hemimethylated DNA.

#### **2.2 DNA methylation studies in schizophrenia**

Initial studies on DNA methylation differences between SZ patients and controls, and among discordant monozygotic twins focused on candidate genes identified by genetic studies. For example, Abdolmaleky et al. [40] by using DNA from frontal lobes of post-mortem brain samples showed 50% increased methylation in the RELN promoter. Subsequent DNA methylation studies focused on genes involved in Dopaminergic [41], GABAergic [42], Glutamatergic [43], serotonergic pathways [44] of neurotransmission and genes such as BDNF [45]. These studies used DNAs either post-mortem brain samples or peripheral blood lymphocytes. However, the data did not always yield consistent reports. For example, in case of BDNF promoter IV, decreased DNA methylation was observed in peripheral blood in a study by Kordi et al. [46] whereas, Ikegame et al. [47] and Ümit Sertan Çöpoğlu et al. [48] reported no change in the methylation levels in the same tissue. Subsequent studies which used genome-wide methylation analysis identified many genes showing statistically significant differences in DNA methylation, but the effective values or the degree of methylation differences observed were not large enough to demonstrate a biological effect such as altered expression. For example, in one of the first studies, Mill et al. [49] by using microarrays identified genes RPL39 and WDR18 with increased methylation in the promoter upstream regions of 8% and 3%, respectively. Studies conducted after these observations used a variety of technologies such as Methylated DNA Immunoprecipitation (MeDIP) – sequencing and Illumina-27 K and 450 K arrays and reported differentially methylated sequences with low effective values. Importantly these studies identified genes with little or no overlap among the top gene hits corresponding to the most significant differentially methylated sites [50]. Nevertheless, some of these genome-wide studies also identified methylation differences in candidate genes such as COMT [51], GAD1, RELN [52] and BDNF [53]. Although these genome-wide studies did not yield common genes with significant differences in DNA methylation, bioinformatic analyses revealed common pathways. For example, methylome data using the blood DNAs revealed the involvement of functioning of the immune system [54]. This in turn is in agreement with the genome-wide association studies that identified immunerelated genes including the major histocompatibility locus [55]. Another common pathway identified in both blood– and DNA- based studies is the neurodevelopmental processes [56]. The DNA methylation studies were also extended to study the effects on gene expression. In one such study, Liu *et al*. [57] identified 16 differentially methylated sites using a case–control approach. When the corresponding 16 genes were studied only five genes showed an inverse correlation of expression with methylation whereas two showed a positive correlation. The remaining genes showed no difference in the level of expression. Besides analysis of gene-related regions of the genome, bulk DNA methylation in SZ patients was also investigated. In such studies, Bonsch *et al*. [58] observed lower levels of methylation in peripheral blood monocytes of patients among discordant monozygotic twins. Meals *et al*. [59] also found a decreased global methylation levels in leukocytes of patients compared to normal individuals. However, these studies are not in agreement with Bromberg *et al*. [60] who did not observe any difference in the global methylation levels in leukocytes. Overall studies on the global methylation levels were inconclusive and likely to be influenced by factors such as age, gender, medication and smoking behavior. In summary, some but not all studies observed

significant differences in DNA methylation levels in the candidate genes whereas genome-wide studies indicated the involvement of neurodevelopmental processes and immune system function. These results are consistent with the model of etiology that SZ is a complex disorder with no single causative factor.

#### **2.3 Dysregulated DNMTs in schizophrenia**

Epigenetic processes and epigenetic modifications are tightly controlled to enable normal mammalian development. In this context, the presence of aberrant DNA methylation patterns affecting the candidate genes suggests the possibility of the role of dysregulation of epigenetic machinery in SZ. Investigations on dysregulation of DNA methylation machinery in SZ dates back to 2005 when Veldic *et al.* [61] reported increased DNMT1 levels in the GABAergic interneurons of postmortem brain tissues of SZ patients. This increase was also correlated with increased promoter methylation and decreased expression of *REELIN,* an extracellular matrix protein and *GAD67*, an enzyme involved in production of GABA. Importantly, DNMT1 inhibitors were reported to decrease hypermethylation and increased expression of the two genes [62]. Subsequently, HDAC inhibitors were also shown to relieve the repression associated with DNMT1 overexpression to an extent similar to DNMT1 inhibitors [63]. These results suggest the potential of epigenetic drugs in ameliorating the phenotypes associated with SZ. Later experiments in brain tissues of patients revealed that at increased levels, DNMT1 binds to *REELIN*, *GAD67* and *BDNF* promoters in cortex but not cerebellum. Further, this selective cortex-specific binding is not associated with any changes in the levels of DNA methylation [64]. The authors suggested that increased DNMT1-associated downregulation of the three genes can be independent of the catalytic activity of DNMT1. As mentioned above, DNMT1 is a maintenance methyltransferase and cannot introduce new methyl groups in the DNA. Therefore, hypermethylation of *REELIN* and *GAD67* is possible only if there is *de novo* methylation followed by maintenance methylation of DNMT1. Not surprisingly, overexpression of DNMT1 as well as DNMT3A was subsequently observed in post-mortem brain samples as well as peripheral blood lymphocytes of SZ patients [65]. Further, DNMT3B overexpression was also reported in peripheral blood lymphocytes but is not reported as of date in post-mortem brain tissues of SZ patients. Since both DNMT3A and 3B are required for *de novo* methylation, it is not unexpected that DNMT3B would also be overexpressed in the brain tissues of the patients. In addition to human studies, experiments using offspring of prenatal restrained stressed mice also confirmed the association of increased DNMTs with SZ-associated phenotypes. In the progeny, DNMT1 and 3A protein levels were high with increased binding of DNMT1 and MeCP2 (Methyl-CpG binding protein 2) and repression of *REELIN* and *GAD67* promoters [66].

Taken together, there is reasonable argument for DNMT1 and DNMT3A and, possibly DNMT3B overexpression as risk factors for SZ. However, the information on the number of genes dysregulated due to DNMT1 overexpression was limited only three (*REELIN, GAD67* and *BDNF*). By taking DNMTs as risk-conferring genes, Saradalekshmi *et al*. [67] investigated whether any SNPs of DNMTs are associated with SZ. In this case–control study, minor alleles at rs2114724 and rs2228611 of *Dnmt1*, rs2424932 and rs1569686 of *Dnmt*3B and rs2070565 in *Dnmt3L* showed significant association with SZ. The authors also reported that rs2424932 showed an association in male patients whereas rs1569686 was associated with an earlier onset in patients with family history. Bioinformatic analysis on the effects of these SNPs suggested that the minor alleles affect the splicing of *Dnmt1* or *Dnmt3L*

transcript or reduce the levels of expression of *Dnmt3B*. However, functional studies on these SNPs were not reported yet.

#### **2.4 Models of dysregulated DNMTs**

In the light of reports suggesting increased DNMT1 and/or DNMT3A levels as risk factors for SZ, it is important to understand the effects of their overexpression on neurodevelopment. Unfortunately, overexpression of DNMT1 results in midgestational lethality in mice [68] making it impossible to generate animal models with constitutive overexpression. In addition, reduction of DNMT1 protein levels, but not its absence, appears to be an essential step for differentiation [69]. In this context, it is also difficult to generate mice conditional alleles of *Dnmt1* that enable neurogenesis-specific overexpression. Therefore, we proposed that cell-based models that either over express DNMT3A or DNMT1 or together serve as useful tools for studying the effects on neurogenesis. Specifically, embryonic stem cells (ESCs) are attractive because they provide opportunities to investigate the effects of DNMT1 and /or DNMT3A overexpression at different stages of neural differentiation. For instance, during the induction of neuronal differentiation, the ESCs are first differentiated into embryoid bodies (EBs) to obtain progenitor cells with ectoderm, endoderm and mesoderm specification. From EB stage, the cells can be differentiated into neuronal progenitor cells (NPCs) and subsequently into neurons.

In order to study the effects of DNMT1 overexpression on neurogenesis, D'Aiuto *et al*. [70] utilized *Dnmt1tet/tet* (*Tet/Tet*), a mouse embryonic stem cell line that overexpresses DNMT1 (**Figure 2A**). This cell line was generated by insertion of *tetoff* cassettes between the *Dnmt1* promoters and the start codons of both chromosomes [71]. As a result, the endogenous *Dnmt1* promoter expressed tTA, a transactivator that binds to the CMV-*tet operator* (*TetO + CMV* sequence present at the 3<sup>0</sup> -end of the *tet-off* cassettes. This resulted in increased expression of DNMT1 in the *Tet/Tet* ESCs. When doxycycline is added to this cell line, tTA became inactive and could not express *Dnmt1* and making the genome hypomethylated. When the *Tet/Tet* ESCs were used for neuronal differentiation by the authors, there was reduction in DNMT1 levels in embryoid bodies with no difference between the wild-type (*R1*) and *Tet/Tet* cells. However, neurons differentiated from the *Tet/Tet* cells showed abnormal dendritic branching (**Figure 2B**), increased activity of Nmethyl-D-aspartate (NMDA) receptor (**Figure 2C**) and increased levels of the NR1 subunit of the receptor. In this study, the authors reported that increased DNMT1 levels did not result in any hypermethylation of *Reelin* or *Gad67* promoters. This finding was not surprising because DNMT1 was only a maintenance methyltransferase and new methylation marks are established only by the *de novo* methyltransferases. Although this study indicated that DNMT1 overexpression results in abnormal neurogenesis, the effects on the levels of SZ-associated gene transcripts, particularly on genes such as *Gad67*, *Reelin* and *Bdnf* were not investigated.

In a recent study, Saxena *et al*. [72] used a modified neuronal differentiation method that resulted in increased expression of DNMT1 in *Tet/Tet* neurons (**Figure 2D**). These results suggested that *Tet/Tet* neurons were suitable for studying the expression levels of SZ-associated genes in presence of increased DNMT1 levels [73]. When 15 SZ-associated genes were tested between the *Tet/Tet* and *R1* neurons, 13 showed significantly altered transcript levels of which, 11 showed identical patterns of dysregulation as in patients (**Figure 2E**). Eight of these 11 also showed significantly altered transcript levels in *Tet/Tet* ESCs but the patterns were similar to *Tet/Tet* neurons in only five cases. These results suggested that the dysregulation patterns of the SZ-associated genes varied during the stages of

*DNA Methyltransferases and Schizophrenia: Current Status DOI: http://dx.doi.org/10.5772/intechopen.98567*

#### **Figure 2.**

*(A) Generation of* Tet/Tet *ESC line.* R1*: wild-type. Oocyte (1o), somatic cell (1s) and pachytene spermatocyte (1p) promoters are shown. (B) Embryoid bodies (EBs) and neurons differentiated from* R1 *and* Tet/Tet *ESCs. Neo/Pur: Neomycin and puromycin selection markers. (C) Increased NMDA receptor activity in* Tet/Tet *neurons. Compared to* R1 *neurons, when glutamate was added, the calcium uptake is higher in* Tet/Tet *neurons. This uptake is inhibited when MK801 (inhibitor of NMDA receptor) was used. (D) Western blot analysis of DNMT1 in* Tet/Tet *ESCs, EBs and neurons. (E) Four distinct categories of the 15 SZ-associated gene transcripts studied in* Tet/Tet *and* R1 *cells. Direction of change is indicated as per the color key. Red color indicates decreased transcript levels whereas increased transcript levels are shown in blue. Absence of color indicates no change.*

pluripotency and neuronal differentiation. The authors then used doxycycline to turn off *Dnmt1* and studied whether dysregulation observed in *Tet/Tet* ESCs could be reversed. Out of the eight genes tested in ESCs, the direction of transcript dysregulation for only four genes was reversed. These results suggested that by using DNMT1 inhibitors, it may not be possible to reverse DNMT1 overexpressionassociated dysregulation of certain SZ-associated genes. Importantly, in this study, the authors did not observe any significant difference in the levels of methylation of the promoters of the affected genes either in ESCs or neurons. These results indicated that dysregulation of the genes studied in *Tet/Tet* neurons could be due to catalytic activity-independent effects of DNMT1. While the results on the *Tet/Tet*

cells undoubtedly revealed the effects of DNMT1 overexpression on a wider set of SZ-associated genes, details on the global effects of increased DNMT1 levels at the transcriptome and methylome levels are still awaited.

#### **3. Conclusions**

In conclusion, molecular details that connect DNMT1 overexpression with abnormal neurogenesis are beginning to emerge. With the availability of genomewide methylation and transcriptome analysis methods, it is now possible to investigate the effects of DNMT1 overexpression in post-mortem brain samples of SZ patients. However, this effort requires an understanding on the incidence of DNMT1 overexpression in these samples. Of particular interest is to compare the effects of overexpression of DNMT1 or DNMT3A or both during the process of neuronal differentiation and the nature of the altered transcript levels. Whether the genes affected are only related to SZ or other neuropsychiatric disorders or neurodevelopmental disorders is an important question that needs to be addressed. Such information is useful to explore the contribution of epigenetic mechanisms in a wider spectrum of neurological disorders. In addition, improvement in the methods for generating genetically modified ESCs, their differentiation into specific types of neurons and development of brain organoids should help advance our understanding of the relationship between dysregulation of DNA methyltransferases and neurodevelopmental disorders such as schizophrenia.

#### **Acknowledgements**

Work in KNM's laboratory is supported by grants from Science and Engineering Research Board, Department of Biotechnology and Birla Institute of Technology and Science Pilani. PAM received fellowship from a project funded by the Department of Biotechnology and later from Centre for Human Disease Research (BITS Pilani). KNM received OPERA award (BITS Pilani) and partial funding from the Centre for Human Disease Research.

#### **Conflict of interest**

The authors declare no conflicts of interest.

*DNA Methyltransferases and Schizophrenia: Current Status DOI: http://dx.doi.org/10.5772/intechopen.98567*

#### **Author details**

Pranay Amruth Maroju<sup>1</sup> and Kommu Naga Mohan1,2\*

1 Department of Biological Sciences, BITS Pilani Hyderabad Campus, Hyderabad, India

2 Centre for Human Disease Research, BITS Pilani Hyderabad Campus, Hyderabad, India

\*Address all correspondence to: mohankn@hyderabad.bits-pilani.ac.in

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## *Edited by Kenjiro Fukao*

Psychosis has been the central subject of psychiatric research for more than a century and yet it remains an intriguing enigma. This volume reviews the current status of research on psychosis in three different aspects, namely, phenomenology, which is the philosophical/conceptual basis of psychosis; psychopathology, which is the clinical manifestations of psychosis; and pathophysiology, which is the scientific pursuit for the mechanism of psychosis. Chapters focus on schizophrenia, covering such topics as clinical staging, negative symptoms, epigenetics, DNA methyltransferases, and more.

Published in London, UK © 2022 IntechOpen © idmanjoe / iStock

Psychosis - Phenomenology, Psychopathology and Pathophysiology

Psychosis

Phenomenology, Psychopathology

and Pathophysiology

*Edited by Kenjiro Fukao*