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The Clues in Solving The Mystery of Major Psychosis: The Epigenetic

Basis of Schizophrenia and Bipolar Disorder

Çevik Gürel, Gökçe Ceren Kuşçu, Altuğ Yavaşoğlu, Çığır Biray Avcı

PII: S0149-7634(19)31046-2
DOI: https://doi.org/10.1016/j.neubiorev.2020.03.005
Reference: NBR 3720

To appear in: Neuroscience and Biobehavioral Reviews

Received Date: 12 November 2019

Revised Date: 19 February 2020
Accepted Date: 4 March 2020

Please cite this article as: Gürel Ç, Kuşçu GC, Yavaşoğlu A, Avcı ÇB, The Clues in Solving
The Mystery of Major Psychosis: The Epigenetic Basis of Schizophrenia and Bipolar Disorder,
Neuroscience and Biobehavioral Reviews (2020),
doi: https://doi.org/10.1016/j.neubiorev.2020.03.005

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Title Page

Title: The Clues in Solving The Mystery of Major Psychosis: The Epigenetic Basis of Schizophrenia and
Bipolar Disorder

Running Title: Epigenetic Basis of Major Psychosis

Çevik Gürel1,2 Gökçe Ceren Kuşçu1* Altuğ Yavaşoğlu1 Çığır Biray Avcı3

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1
Ege University, Faculty of Medicine, Department of Histology and Embryology, İzmir, 35100,
Turkey

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2
Harran University, Faculty of Medicine, Department of Histology and Embryology, Şanlıurfa, 63100,
Turkey

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Ege University, Faculty of Medicine, Department of Medical Biology, İzmir, 35100, Turkey
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*Corresponding author: Gökçe Ceren Kuşçu (MSc)
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E-mail address of the corresponding author: gokce.ceren.kuscu@gmail.com

Postal address of the corresponding author: Faculty of Medicine, Department of Histology and
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Embryology, Ege University, 35100, Bornova - İzmir, Turkey.

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Highlights

 Findings show that epigenetic mechanisms may contribute to the emergence of major psychosis
 Epigenetic markers can be used in the diagnosis of major psychosis
 Management of epigenetic modifications may be the key to “personalized treatment” in the major
psychosis

Abstract

Schizophrenia (SZ) and bipolar disorder (BD) are severe psychiatric diseases that are characterized by

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abnormalities of thought, behaviour, cognition and mood. The genetic findings obtained from past

molecular genetics research failed to elucidate the molecular pathogenesis of SZ and BD and this

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situation showed that the risk factors for these diseases were not solely due to the DNA sequence. On

the other hand, evidence from cell, animal and postmortem brain studies suggest that abnormal
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epigenetic mechanisms are important actors in the etiology of complex diseases such as SZ and BD. In

this review, epigenetic evidences that obtained from DNA methylation, post-translational histone
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modifications and non-coding RNA studies in SZ and BD were summarized and the importance of this
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evidences for advances in the diagnosis and treatment of SZ and BD were discussed briefly.

Key Words: schizophrenia, bipolar disorder, DNA methylation, histone modification, non-coding
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RNA

1. Introduction
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Schizophrenia (SZ) and bipolar disorder (BD) are psychiatric diseases characterized by severe and

chronic thought, behavior, cognition and mood abnormalities that are thought to have similar
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etiologies. These diseases are called "major psychosis" together and affect approximately 2% of the

world's population (Steardo et al., 2019; Yu et al., 2019). The family, twin and adoption studies on SZ

and BD, which are thought to originate in abnormalities in brain development that cause brain circuits

to deteriorate, have revealed the importance of genetic factors in the neuropathology of major

psychosis (Duan et al., 2019; Hoffman et al., 2019). In these studies, the concordance of SZ and BD in

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monozygotic twins have been found to be approximately 50% and 80%, respectively. Also, gene

polymorphisms and loci, which are thought to play a role in these disorders, have been defined in

genetic studies (Akbarian and Huang, 2009; Alelú-Paz et al., 2015; Nestler et al., 2016). However,

these genetic findings have been inadequate to elucidate the etiology of major psychosis and this

situation has shown that risk factors for major psychosis are not derive merely from the DNA

sequence (Hoffman et al., 2019). Besides, recent evidence suggests that epigenetic modifications such

as DNA methylation, posttranslational histone modifications and non-coding RNA have an important

role in the etiology of major psychosis (Gescher et al., 2018).

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In this review, we aim to summarize scientific studies from past to present on the epigenetic

modifications in SZ and BD to understand the role of these modifications in the molecular etiology of

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the major psychosis.

2. Epigenetics: An Overview -p
Epigenetics, which means etymologically “above” or “beyond” of genetics, was first described by
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Conrad Hal Waddington as "the branch of biology that studies the causal interaction between genes

and their product, which bring the phenotype into being" (Begolli et al., 2019; Qi et al., 2019).
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Nowadays, epigenetics refers to the patterns of gene transcription changes that occur without

alterations in the DNA sequence (Qi et al., 2019; Quintanal-Villalonga and Molina-Pinelo, 2019).
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Gene expression changes resulting from epigenetic modifications can be inherited by mitosis and

meiosis. In other respects, epigenetic is a dynamic process and epigenetic modifications are reversible
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as opposed to genetic changes (Föcking et al., 2019; Wróblewski et al., 2019). By the help of their

dynamic and reversible nature, epigenetic modifications that make up an "extra" transcriptional control
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layer in cells undertake important roles in biological processes such as development, cellular

differentiation, initiation and maintenance of tissue-specific gene expression (George et al., 2019; Qi

et al., 2019). There are three main mechanisms involved in the regulation of epigenetic modifications

in mammals: i) DNA methylation ii) posttranslational histone modifications, and iii) non-coding

RNAs (Chen et al., 2019; George et al., 2019).

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2.1. DNA Methylation: Same Gene but Different Transcription Patterns

DNA methylation is the first described and most studied epigenetic mechanism in mammals, including

human. DNA methylation is a covalent modification and this is characterized by the formation of a 5-

methyl cytosine (5mC) structure by attaching a methyl group to the 5C of the cytosine followed by

guanine (CpG) (Quintanal-Villalonga and Molina-Pinelo, 2019). The family of enzymes called DNA

methyltransferases (DNMTs) is responsible for the formation and maintenance of the DNA

methylation pattern. The main task of DNMTs having four types in humans (DNMT1, DNMT3A,

DNMT3B and DNMT3L) is to transfer a methyl group from the universal methyl donor S-adenosyl

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methionine (SAM) to the CpG dinucleotide (Chen et al., 2019; Lyko, 2017). CpG dinucleotides in

which the methyl group is transferred, are not randomly distributed in the human genome and are

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predominantly concentrated in "CpG islands" located at gene promoters. Hypermethylation of CpG

islands which are normally hypo or unmethylated leads to transcriptional inactivation of associated
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gene. The suppression of gene expression by CpG dinucleotides methylation is a fundamental

phenomenon in physiological processes, including inactivation of X chromosome in women,

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regulation of germline-specific genes, and silencing of non-tissue-specific genes (Begolli et al., 2019;
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Föcking et al., 2019). Still, DNA methylation is not seen only in CpG islands. The second type of

DNA methylation (cytosine methylation; 5mC) is observed at the gene body and gene-body DNA

methylation is associated with the activation of genes in contrast to the methylation observed in CpG
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islands (Greenberg and Bourc’his, 2019). Gene body methylation plays key roles in preservation of

chromosomal integrity and inhibition of endoparasitic sequences reactivation (Greenberg and

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Bourc’his, 2019; Pfeifer, 2018).

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In the past, DNA methylation was believed to be an irreversible and static epigenetic event related to

gene repression, which could only be alleviated by DNA replication (Rasmussen and Helin, 2016).

Today, however, it is known that DNA methylation is a highly dynamic process. Indeed, studies have

shown that ten eleven translocation (TET) proteins (TET1, TET2, TET3) can modify 5mC and

potentially erase DNA methylation. TET1, TET2, and TET3 catalyze the successive oxidation of 5mC

in DNA to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC)

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(An et al., 2017; Rasmussen and Helin, 2016). The process of converting 5mC to 5hmC and

subsequent oxidized derivatives is called “demethylation”. The methylation-demethylation balance is

critical in the heredity of epigenomic information to generation and in the continuity of cellular

homeostasis (Arechederra et al., 2018; Rasmussen and Helin, 2016). On the other hand, the disruption

of the methylation-demethylation balance prepares the ground for many diseases, especially cancer.

Also,findings show that DNA methylation are important for multiple neurobiological processes such

as neurogenesis, learning, and memory (Jobe and Zhao, 2016; Rasmussen and Helin, 2016; Wang et

al., 2016). As a result of these observations, it can be assumed that abnormal DNA methylation may

contribute to the etiopathogenesis of many neurological and psychiatric disorders (Greenberg and

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Bourc’his, 2019; Ovenden et al., 2018).

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2.2. Post-translational Histone Modifications: Guardians of Access to Genetic Information

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A second epigenetic mechanism is post-translational histone modifications that control dynamic

transitions between transcriptionally active (euchromatin) and inactive (heterochromatin) chromatin

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structures (Chen et al., 2019; Wang et al., 2019). Besides being involved in transcriptionally active or

inactive chromatin structures, histone modifications affect transcriptional accuracy through the
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regulation of DNA repair, alternative splicing, transcription and genome stability (Snyder and Gao,

2019). In this context, post-translational histone modifications appear to be significant actors in the
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establishment and maintaining of specific gene transcription patterns (Christopher et al., 2017;

Henning et al., 2018; Yan et al., 2019).

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Today, a variety of posttranslational histone modifications have been defined including acetylation,

methylation, phosphorylation, ubiquitination, SUMOylation, O-GlcNAcylation and ADP-ribosylation,

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which associated with both transcriptional inhibition and activation. However, a great majority of the

literature has focused on acetylation, phosphorylation and methylation from these modifications (Chen

et al., 2019; Shanmugam et al., 2018).

Histone acetylation is a covalent and reversible histone modification carried out by histone

acetyltransferases (HATs), which transfer an acetyl group from acetyl CoA to positively charged

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lysine residues located on histone tails (Bonnaud et al., 2016; Hałasa et al., 2019). The neutralization

of lysine residues by acetylation leads to a decrease in the affinity of histone proteins to DNA,

resulting in a more relaxed and accessible chromatin structure (Li et al., 2018). Histone acetylation is

associated with gene transcription activation due to the facilitation of access of the transcription

factors to gene promoters by destabilization of the chromatin structure (Borodinova et al., 2019). This

modification, which have an essential role in the regulation of cell cycle, energy metabolism and

cytoskeletal dynamics, is a reversible and dynamic process as mentioned above (Bonnaud et al., 2016;

Chen et al., 2019; Qi et al., 2019). Histone deacetylases (HDACs), which remove the acetyl groups

from acetylated histones, neutralize the effects of HATs and return histone to its basal state (Chen et

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al., 2015). Deacetylation on the lysine residues of the histone induced by HDACs is associated with a

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compact chromatin structure and limitation of access of the transcription factors to a gene, hence

histone deacetylation leads to gene silencing (von Knethen and Brüne, 2019). Therefore, HDACs are
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thought to act as transcriptional protectors, opposite to HATs. The balance between histone acetylation

and deacetylation controls various physiological processes, and the disruption in this balance
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contributes to the emergence of many pathological conditions, particularly cancer (Chrun et al., 2017;

Singh et al., 2019). Additionally, there is various evidence indicating the role of aberrant histone
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acetylation in the pathogenesis of psychiatric disorders (Chen et al., 2018).

Histone phosphorylation resulting from the addition of phosphor groups by protein kinases to
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threonine, tyrosine and serine residues in histone tails is an important modification contributing to the

dynamic chromatin structure (Qin et al., 2019). Histone phosphorylation is reversible just like histone
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acetylation, and this modification has been closely associated with several cellular events including

mitosis, chromosome condensation, cell cycle regulation, DNA repair, cellular stress response, and
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apoptosis (Batista and Helguero, 2018; Qin et al., 2019). The content and region of histone

phosphorylation determines the cellular process in which this modification plays a role. For example,

H2AX Ser139 phosphorylation is closely connected with the repair of double-strand DNA breaks,

while H2B Ser14 phosphorilation has been shown to be associated with the condensation of chromatin

associated with apoptosis (Batista and Helguero, 2018; Shanmugam et al., 2018).

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Histone methylation is a complex and subtle designed modification catalyzed by histone

methyltransferase (HMT) carrying a methyl group derived from SAM on a lysine (Lys or K) or

arginine (Arg or R) residue of histone tail (Jambhekar et al., 2019; Monaghan et al., 2019). In

mammalians, the lysine (K) and arginine (R) residues of histone H3 serve as primary acceptor sites of

methylation marks. These methylation marks have varying effects on transcriptional activation or

repression depending on the degree and pattern of methylation. For example, histone 3 lysine 4 tri-

methylation (H3K4me3) and H3K27me3 are generally associated with gene activation and increased

transcription, while H3K9me2 is found more commonly at silent or lowly expressed genes in

euchromatin (Jambhekar et al., 2019).

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Histone methylation is also a dynamic process such as other histone modifications, and methyl groups

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are removed by with histone demethylase (HDM) (Yan et al., 2019). The balance between the activity

of HMTs and HDMs facilitates the maintenance of histone methylation levels. Disruption of this
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balance can cause gene mutations, translocations and dysregulated expressions, leading to a number of

diseases including cancer (Javaid and Choi, 2017; Yan et al., 2019). At the same time, alterations in
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histone methylation contribute to changes in gene expression patterns in the brain and these alterations
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are closely related to the etiopathogenesis of mood and psychosis spectrum disorders (Peter and

Akbarian, 2011).
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2.3. Non-Coding RNAs: Master Regulators of Genetic Information Stream

Another epigenetic mechanism is the RNA interference (RNAi) that regulates sequence-specific
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silencing of target genes via the destabilizing and/or degradation of mRNAs. Therefore, this

mechanism could cause reducing transcription and repression of translation (Setten et al., 2019).
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Although new RNA classes have been discovered in the RNAi mechanism with each passing day,

there are two small non-coding RNA (sncRNA) classes that are closely related to this mechanism:

micro RNAs (miRNAs) and short-interfering RNAs (siRNAs) (Zotti et al., 2018). The structurally and

functionally similar miRNAs and siRNAs differ from each other at several points. For example,

miRNAs are assumed as endogenous and voluntary expressed products of cells, whereas siRNAs are

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considered to be exogenous products derived from viruses, transposons or transgenes trigger. On the

other hand, a siRNA is exactly complementary to a single sequence in the target mRNA, this situation

cause the cleavage of the mRNA and inhibiting the target gene expression. Nevertheless, a miRNA

has a partial complementarity to the target mRNA by the stem-loop sequence at the 5 'end, which

means that one miRNA may have more than one target. Furthermore, miRNAs inhibit the translation

of an mRNA as opposed to siRNAs (Lu et al., 2019; Zotti et al., 2018). It is known that dysregulated

expressions of miRNAs that have important functions in regulating many basic cellular activities

under normal physiological conditions are important in the etiology of many diseases, particularly

cancer, neurodegenerative, and psychiatric diseases (Autin et al., 2019; Lu et al., 2019; Narahari et al.,

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2017).

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A different class of the ncRNA family is the long-non coding RNAs (lncRNAs). Length of lncRNAs

is over 200 nucleotides and these RNAs are endogenous cellular transcripts that represent a large
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portion of the ncRNA pool (Begolli et al., 2019; Ju et al., 2018). The lncRNAs use different

mechanisms to control their activity in cells such as regulating transcription through changing of
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chromatin structure by interacting with DNA, mediating alternative splicing of the mRNA and
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affecting the stability of mRNA via binding to transcripts or removing miRNA (Begolli et al., 2019;

Gibbons et al., 2018). Findings from studies on lncRNAs indicate that this RNA class is directly

involved in biological processes such as cell integrity maintenance, cell cycle regulation, inactivation
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of the X chromosome and genomic imprinting (Kim et al., 2016; Sun and Wang, 2019). Additionally,

growing evidence highlighted that lncRNAs are associated with the etiopathogenesis of psychiatric
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diseases (Fang et al., 2018; Yuan et al., 2018).

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3. Epigenetic Aspect of SZ and BD

Epidemiological and clinical evidence that neuropathogenesis of SZ and BD do not comply with the

expected rules for a Mendelian-genetic disorder has led to suggesting that epigenetic mechanisms such

as gene-specific DNA methylation, posttranslational histone modifications, and non-coding RNAs

may play an important role in the emergence of major psychosis (Duffy et al., 2019; Mendizabal et al.,

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2019). Cell, animal and postmortem brain studies conducted to reveal the epigenetic basics of major

psychosis support the claim that complex diseases such as SZ and BD may be a phenotypic

manifestation of abnormal epigenetic mechanisms (Figure 1). In this part of the review, a summary of

studies aiming to solve the epigenetic infrastructure of SZ and BD will be convey.

>Figure 1<

3.1. DNA Methylation Alterations in SZ and BD

To date, DNA methylation alterations have been the most studied epigenetic mechanism in major

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psychosis. The initial studies investigating the relationship between DNA methylation alterations and

major psychosis were focused on disease-related genes such as DRD2, MB-COMT, RELN, GAD1,

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and SOX10 (Grayson and Guidotti, 2013; Zhao et al., 2015). Among these genes, RELN and GAD1

have been most associated with abnormal methylation in major psychosis. The RELN gene expresses
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an extracellular matrix glycoprotein reelin, an important function in directing neurons and radial glial

cells to their correct position in the developing brain (Lee and D’Arcangelo, 2016). GAD1 expresses
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the glutamic acid decarboxylase 67 (GAD67) which catalyzes the conversion of L-glutamate to the

inhibitor neurotransmitter γ-amino butyric acid (GABA) (Magri et al., 2018). Veldic et al.
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demonstrated that DNMT1 overexpression in telencephalic GABAergic interneurons of postmortem

SZ patients’ brains resulted in hypermethylation in RELN and GAD1 gene promoters, leading to a
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decrease in reelin and GAD67 mRNA and protein expression (Veldic et al., 2004). In a study with

similar results, GAD1 and RELN hypermethylation and GAD67 and reelin mRNA downregulation
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were determined in the prefrontal GABAergic neurons of SZ and BD patients due to DNMT1 and

SAM overexpression in prefrontal GABAergic neurons (Guidotti et al., 2007). In paralel with
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postmortem brain studies, L-methionine-induced mouse SZ model have shown that DNA

hypermethylation leads to a decrease in the level of expression of the reelin and GAD67 and to

chromosomal remodeling in cortical GABAergic interneurons (Dong et al., 2005). However, a study

conducted by Tochigi et al. in Japan reported there was no significant RELN promoter

hypermethylation in neither gray nor white matter of brain tissues of schizophrenia patients (Tochigi et

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al., 2008). Another recent study on MMP9, which play a role in the regulation of the extracellular

matrix, has shown that the gene region encoding this protein is hypomethylated in deficit SZ patients

compared to non-deficit SZ patients (Gao et al., 2018).

In 2010, Tolosa et al. showed that the level of FOXP2 methylation in the left parahippocampal area

was higher compared to the right parahippocampal area in postmortem brain tissues of SZ patients. In

the same study, the authors argued that SNPs and impaired methylation patterns observed in the

FOXP2 gene, which is known to be associated with the correct development of speech and language,

may be associated with language disorders observed in SZ patients (Tolosa et al., 2010).

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In a study on BD vs Alzheimer's disease (AD), researchers found that the COX-2 promoter CpG

region showed decreased methylation in both AD and BD brains (Rao et al., 2012). In another article

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published in the same year, it was revealed that the MAOA gene, responsible for neurotransmitter

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metabolism, methylation levels did not significantly differ between paranoid SZ patients and the

control group (Chen et al., 2012).

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In addition to these studies, another study by Zhubi and colleagues reveals that another enzyme

involved in DNA methylation, DNMT3a, is significantly overexpressed in both GABAergic

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interneurons and peripheral blood lymphocytes of SZ patients (Zhubi et al., 2009). Also, it was

founded that TET1 mRNA and protein expression increased in the parietal cortices of SZ and BD
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patients. This increase is associated with an increased genome-wide level of 5hmC and also an

increase in 5hmC levels at GAD67 and BDNF promoters (Dong et al., 2012). Additionally, the study
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on prenatal restraint stress (PRS) mice which exhibit the schizophrenia-like biochemical and

behavioral abnormalities revealed that brain of these mice characterized by increased DNMT1 and
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TET1 expression levels exhibit an enrichment of 5hmC at neocortical GABAergic and glutamatergic

gene promoters (Matrisciano et al., 2016).

Another gene shown to contribute to the etiopathology of the major psychosis of the methylation

change pattern is the membrane encoding catechol-O methyl transferase (MB-COMT) that is

responsible for the dissimilation of neurotransmitters such as dopamine and noradrenaline. The

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evidence that the MB-COMT gene promoter methylation is more common in the postmortem brains of

patients with SZ and BD compared to controls shows that this may increase the risk of major

psychosis (Abdolmaleky et al., 2006). Similarly, Nohesara et al. showed that the MB-COMT promoter

was hypomethylated in DNA derived from saliva samples of SZ and BD patients, just as in

postmortem brains. This group also suggested that analysis of MB-COMT promoter methylation status

in saliva samples could be used as a proper epigenetic biomarker for diagnosis of major psychosis

(Nohesara et al., 2011). In a study of SZ patients and healthy controls, functional magnetic resonance

imaging results point to a positive correlation between MB-COMT promoter methylation and left

dorsolateral prefrontal cortex. In the same study, it was emphasized that this correlation was

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independent of the disease state and suggested that neuroimaging of MB-COMT promoter DNA

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methylation could be used to establish the relationship between MB-COMT promoter methylation and

SZ (Walton et al., 2014). On the other hand, contrary to the above studies Dempster et al., emphasized
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that there was no any alteration in COMT methylation or expression in examined SZ and BD samples.

(Dempster et al., 2006).

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Microarray-based study to systematically identify the DNA-methylation changes in frontal cortex of
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major psychosis patients revealed that genes such as WDR18, GRIA2 and MARLIN-1 showed

hypomethylation patterns in BD and SZ. Second important finding of this study is that the genes

involved in neurodevelopment such as WNT1 and NR4A2 showed DNA methylation alteration
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specifically in female patients. Also, this study revealed that female BD patients showed

hypermethylated KEL status compared to SZ patients and control (Mill et al., 2008).
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In studies on potassium ion channels-related molecules, KCNJ6 (Mill et al., 2008) and KCQN3
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(Kaminsky et al., 2015) have been shown to exhibit a hypomethylation pattern in major psychosis.

Studies on synaptic plasticity-related molecules revealed that GRIN-2B is hypomethylated in SZ

patients (Fachim et al., 2019), while EGR-1 methylation patterns have no significant difference

between SZ patients and control (Hu et al., 2019).

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Genome-wide methylation analysis of brain tissues of schizophrenia patients revealed that genes such

as NOS1 and AKT1, previously associated with this disease, shown abnormal methylation patterns

(Wockner et al., 2014). In 2015, Abdolmaleky et al. showed that DTNBP1 gene promoter methylation

was significantly higher in patients with SZ and psychotic BD compared to the control group

(Abdolmaleky et al., 2015). In the study of the same group in 2011, the authors revealed that HTR2A

gene was hypomethylated in saliva samples of SZ and BD patients (Abdolmaleky et al., 2011). On the

other hand, Bromberg et al. shown that there was no significant difference between SZ patients and

control group in their global leukocyte methylation analysis (Bromberg et al., 2008).

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In 2017, Jiang et al. showed that DNA methylation level exhibited a gender-dependent positive

correlation with age and the hydroxymethylation level exhibited a correlation with age positively in

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controls but negatively in SZ patients. Interestingly, this study also shown that male SZ patients

displayed a global hyper-hydroxymethylation pattern whereas female SZ patients displayed a global

hypo-hydroxymethylation pattern (Jiang et al., 2017).

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In 2015, Pal et al. shown that human leukocyte antigen (HLA) complex-HCG9 hypomethylated in BD

patients’ brain, sperm and blood (Pal et al., 2015). Interestingly, Burghardt et al. found that skeletal
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muscle global methylation of 5mC and 5fC were significantly higher in BD subjects compared to

healthy controls. This study also reveals that BD patients using mood stabilizers have a higher 5mC
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level compared to patients using atypical antipsychotics (Burghardt et al., 2019).

Sugawara et al. revealed that FAM63B and IR on chromosome 16 were significantly hypometylated in
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both BD and SZ samples. Another interesting finding of the same study was that CpG sites of

TBC1D22A were hypermethylated in BD samples, whereas hypometylated in SZ samples (Sugawara

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et al., 2018). In 2019, Pai et al. reported that significant hypomethylation of an enhancer in the insulin-

like growth factor 2 (IGF2) gene was observed in major psychosis neurons. Chromatin conformation

analysis from the same study revealed that this enhancer targeted the tyrosine hydroxylase (TH) gene

which responsible for dopamine synthesis (Pai et al., 2019).

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Recently, another study on the blood and brain tissues of SZ patients emphasized that DDR1

hypermethylation in leukocytes and brain tissue could be associated with psychosis, physiological

stress and inflammation (Garcia-Ruiz et al., 2020).

The gene methylation alterations which revealed with studies are shown in Table 1 (Abdolmaleky et

al., 2011; Chen et al., 2012; Çöpoğlu et al., 2016; Fachim et al., 2019; Gao et al., 2018; Hu et al.,

2019; Kaminsky et al., 2015; Mill et al., 2008; Nohesara et al., 2011; Pal et al., 2015; Popendikyte et

al., 1999; Rao et al., 2012; Starnawska et al., 2016; Tolosa et al., 2010)

>Table 1<

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Studies on both SZ and BD patients and experimental animals have demonstrated that DNA

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methylation may play a key role in the emergence of major psychosis by altering the expression of

molecules (Figure 2) involved in the regulation of brain functions such as neurogenesis, synaptic

plasticity and neurotransmitter delivery.

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3.2. Aberrant Post-translational Histone Modifications in SZ and BD

3.2.1. Histone Methylation in SZ and BD

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Aberrant posttranslational histone modifications are another epigenetic phenomenon associated with

major psychosis and there are many studies conducted in this context. For example, Akbarian et al.
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showed that downregulated metabolic gene expressions such as CARM1 in the prefrontal cortex of

patients with schizophrenia were associated with methylation of histone H3 arginine 17 (H3R17)
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(Akbarian et al., 2005). Also, in their study on postmortem brains of SZ patients, Huan et al. identified

a decreased histone H3 lysine 4 trimethylation (H3K4me3) in the GAD67 gene, predominantly in

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females (Huang et al., 2007).

In another study shown that H3K9me2 levels were significantly higher in SZ patients compared to

healthy controls. Another striking finding of the same study was the presence of negative correlation

between H3K9me2 and age at onset of the disease (Gavin et al., 2009). In addition, in the genome-

wide profiling of histone methylation analysis on olfactory cells of patients with SZ patients, 72 genes

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were found to be dysregulated due to abnormal levels of H3K4me3 and H3K27me3 (Kano et al.,

2013).

Other study investigating histone methylation in major psychosis suggested that patients with SZ have

increased in the expression of H3K9me2 levels parallel with the G9α, GLP and SETDB1 genes in the

postmortem brain tissues and lymphocytes (Chase et al., 2013). Therewithal, altered levels of

H3K4me3 were detected in the SYN1, SYN2 and SYN3 promoters in the postmortem brains of BD

patients (Cruceanu et al., 2013). In another study showed altered H3K4me3 in Disrupted-in-

Schizophrenia 1 (DISC1), a schizophrenia risk gene often implicated in gene-environment interaction

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models, in polycytidylic acid (polyI:C)-induced schizophrenia-like mouse model (Connor et al., 2012).

In the rat SZ model induced by methylazoxymethanol (MAM), it was found that MAM treatment

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changed H3K9 demethylation levels in the prefrontal cortex of prepubertal rats. In contrast, H3K4

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trimethylation was significantly reduced in adult rats (Maćkowiak et al., 2014). Recently, Hsieh et al.

found that there are no significant change in H3K27me3 level in blood samples of SZ patients
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compared to control samples. On the other hand, same study reported that significantly increased in

BDNF exon IV H3K9me2 levels in SZ patients (Hsieh et al., 2019).

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3.2.2. Histone Acetylation in SZ and BD

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Sharma et al. revealed that H3 and H4 acetylation decreased in SZ compared to BD in lymphocytes

samples from patients with SZ and BD (Sharma et al., 2006). Furthermore, same group found that

histone H3S10p upregulated in peripheral blood mononuclear cells of SZ patients in comparison to

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healthy controls. One of the most striking findings of this study is that the age, sex, race and history of

smoking has no significant effect on H3S10 phosphorylation (Sharma et al., 2015).

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In another study, Tang et al. were compared histone acetylation levels in specific genomic regions of

SZ neuropathology related genes in patients with SZ and BD. In this study found that several genes

associated with schizophrenia, including GAD67 and HTR2C, were hypoacetylated at K9 and K14 in

their promoters in SZ patients (Tang et al., 2011). Additionally, its found that in the polyI:C-induced

schizophrenia-like model, global hyperacetylation of H3 and H4 histones increased in the cortex and

14
hippocampus of polyI:C treated mice compared to sham-treated mice. Also, decreases in acetylation

of histone H3 at K9/K14 were identified at the promoter regions of the glutamate receptor, ionotropic,

AMPA 1 (Gria1), and Roundabout homolog 1 (Robo1) genes, related with abnormally expression of

these genes in polycytidylic acid-treated mice (Tang et al., 2013).

According to the results of their genome-wide analysis on neuronal and neuronal-depleted cells,

Girdhar et al. argued that neuronal H3K4me3 and H3K27ac variants may have a stronger relationship

with schizophrenia than depression and neuroticism. The authors also emphasized the importance of

performing epigenomic fine mapping in the maximum region- and selected cell populations “for the

of
human brain, in order to link the genetic risk architectures of neuropsychiatric disorders to selected

cell populations or neural circuits” (Girdhar et al., 2018).

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In addition to the above studies, Akbarian et al. was reported that H3 serine 10 phosphorylation

-p
(H3S10p) and H3 lysine 14 acetylation (H3K14ac) increased significantly and that these histone

modifications could be related to downregulation of the OAT gene in SZ (Akbarian et al., 2005).
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Investigations on SZ, BD and control cortical brain samples indicated that HDAC1 expression was

significantly higher in SZ samples. Another result of these investigations is that HDAC1, HDAC3, and
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HDAC4 mRNA expression patterns may be strongly or negatively correlated with GAD67 mRNA

expression pattern (Sharma et al., 2008).

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More recently, Ibi et al. showed that paternal valproic acid (VPA), a mood stabilizer with HDACi

activity, exposure can disrupt the balance of histone acetylation in the brain of offspring through
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changes in the germline epigenome, leading to behavioral changes in these offspring (Ibi et al., 2019).
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Evidence from all these studies shows that aberrant posttranslational histone modifications are closely

related to the neuropathology of major psychosis (Figure 2). In fact, many unexplained questions in

genetic studies (i.e twin studies) of major psychosis may be explained by different gene expressions

due to chromatin remodeling regulated by post-transcriptional histone modifications.

3.3. Abnormal Expressions of ncRNAs in SZ and BD

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3.3.1. miRNAs in SZ and BD

In recent years, it has been demonstrated that abnormal miRNA expression may play a crucial role in

etiology of SZ and BD (Kuehner et al., 2019). The first evidence of the role of abnormal miRNA

expression in major psychosis was obtained from study of Perkins et al. In this study were revealed

that 16 miRNAs, including miR-30b were expressed differently in the postmortem brain tissues of SZ

patients compared to the control group (Perkins et al., 2007).

In addition, it was found that global miRNA expression in the prefrontal cortex of SZ patients showed

a significant increase compared to the postmortem superior temporal gyrus and normal controls

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(Beveridge et al., 2010). Moreover, studies have reported an association between the SNPs in the miR-

137 gene and the incidence of schizophrenia (Kuswanto et al., 2015; Strazisar et al., 2015).

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Although most of the studies of abnormal miRNA expression in major psychosis have been
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concentrated in SZ, there are studies investigating the role of miRNAs in the etiology of BD (Azevedo

et al., 2016; Moreau et al., 2011). Kim et al. showed that 15 miRNA were differently expressed in BD
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patients compared to controls (Kim et al., 2010). In another study, it was found that miR-34a

expression increased in the cerebellum of BD patients, and this increase was shown to be associated
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with the onset of the disease and with psychotic symptoms (Bavamian et al., 2015).
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Moreover, Choi et al. found that miR-149 level increased in the extracellular vesicles isolated from

postmortem brain tissues of BD patients compared to the control group (Choi et al., 2017).
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3.3.2. lncRNA in SZ and BD

lncRNAs are another ncRNA family reported by independent studies that may be associated with the
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pathogenesis of major psychosis (Kocerha et al., 2015; Luykx et al., 2017). In the one of these study,

Barry et al. founded that dysregulation of lncRNA Gomafu causes aberrant alternative splicing

patterns in SZ patients (Barry et al., 2014). Similarly, Rao et al. suggested that lncRNA MIAT was

significantly associated with pathogenesis paranoid SZ (Rao et al., 2015). Additionally, Ren et al.

showed that lncRNA abnormalities were significantly related to early-onset SZ (Ren et al., 2015).

16
Also, Sayad et al. reported that CCAT2, TUG1 and PANDA were up-regulated in total BD patients

compared with total healthy subject (Sayad et al., 2019).

Recently, Ni et al. showed that lncRNA-AC006129.1 mediates anti-inflammatory response through

DNA methylation-mediated capicua (a transcriptional repressor) downregulation in SZ (Ni et al.,

2020)

The abnormal ncRNA expressions associated with SZ and BD shown in Table 2 (Banigan et al., 2013;

Barry et al., 2014; Bavamian et al., 2015; Choi et al., 2017; Fallah et al., 2019; Kuswanto et al., 2015;

Lai et al., 2016; Liu et al., 2017; Perkins et al., 2007; Polesskaya et al., 2003; Sayad et al., 2019; Wei

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et al., 2015).

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>Table 2<

>Figure 2< -p
4. Epigenetic Approach To Treatment and Diagnosis of Major Psychosis
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A growing body of studies suggest that alteration in epigenetics mechanisms may undertake a role in
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neuropathologies of major psychosis. In addition, severeal studies are signalized that epigenetic

modification and mechanisms may be important targets for both diagnosis and treatment of major

psychosis. By way of example, Kurita et al. reported that the gene encoding the metabotropic
na

glutamate 2 (mGlu2) receptor was downregulated by histone deacetylation in both the mouse and

human frontal cortex in response to chronic administration of antipsychotic drugs, clozapine and
ur

risperidone (Kurita et al., 2012). The same group found that HDAC2 overexpression in mouse

prefrontal cortex reduced mGlu2 expression and induced behaviors defined as schizophrenia-like. On
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the contrary, chronic administration of histone deacetylase inhibitors (HDACi) such as MS-275 and

SAHA were increased the expression of mGlu2 in the mouse frontal cortex and to protect the

emergence of some psychosis-like phenotypes (Chiechio et al., 2009; Hyman, 2012). However, as

mentioned earlier, paternal use of VPA, another HDACi, may disrupt the balance of histone

17
acetylation in the brain of offspring through changes in the germline epigenome, leading to behavioral

changes in offspring (Ibi et al., 2019).

In another study, Dong et. al. shown that administration in clinically relevant doses of clozapine and

sulpiride (another antipsychotic drug) reduced the methylation of RELN and GAD1 promoter in

frontal cortex and striatum of mice (Dong et al., 2008). Similarly, it was shown that VPA increased

reelin expression following administration of L-methionine and to promoted the acetylation of global

histone H3 in the mouse brain (Tremolizzo et al., 2002). Considering the role of RELN and GAD1

gene alterations in the pathogenesis of SZ and BD and the findings from these studies, it can be argued

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that epigenetics mechanisms and modifications are promising in the treatment of major psychosis.

Another important output of the studies investigating the relationship between major psychosis and

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epigenetics are describing of alterations that can be used in the diagnosis of SZ and BD. Analysis of

-p
peripheral tissues (especially blood) of patients with SZ and BD revealed many epigenetic changes

that differed from healthy subjects. In one of these studies, it has been shown that the promoter
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methylation of the serotonin receptor type-1 (HTR1A) gene is significantly increased in the blood of

SZ and BD patients compared to controls (Carrard et al., 2011). Recently, Sugawara et al. suggested
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that gene hypermethylation of FAM63B and intergenic region on chromosome 16 may be a common

epigenetic risk factor in the pathogenesis of these diseases (Sugawara et al., 2018). Moveover,
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Naghavi-Gargari et al. reported that the expression of DISC1 and DISC2 lncRNA in peripheral blood

mononuclear cells of BD patients was significantly different compared to the control group (Naghavi-

Gargari et al., 2019). In addition, studies on blood, saliva, and sperm samples that can be collected by
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noninvasive methods and giving significant results are listed in Table 1 and Table 2.
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5. Conclusions and Future Directions

A huge amount of studies from past to present clearly showed that epigenetic mechanisms not only

associated with stable changes in brain function and behavior but also have some critical role in

neuropathology of several psychiatric diseases such as SZ and BD (Cariaga-Martinez et al., 2016;

Duan et al., 2019; Hoffman et al., 2019; Roth et al., 2009; Shinozaki et al., 2014). Through the

18
evidence from these studies, epigenetic mechanisms have become an attractive molecular hypothesis

to explain the neuropathology of psychological disorders, particularly major psychosis (Roth et al.,

2009). Although epigenetics provides a new perspective on the etiology of SZ and BD, it would be

"excessive optimism" to expect that applying epigenetic hypothesis to molecular-based studies of

neuropathology is a simple task that can be accomplished without encountering a series of challenges.

For example, the results of RELN methylation analysis in postmortem SZ brains are paradoxical. Two

groups reported increased RELN methylation (Abdolmaleky et al., 2005; Grayson et al., 2005) but two

groups did not (Tamura et al., 2007; Tochigi et al., 2008). This discrepancy may be arising from

methodological problems, such as the process of sodium bisulfite treatment (McGowan and Kato,

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2008). Moreover, postmortem brain studies provide data related to the change of epigenetic

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mechanisms in the brains of SZ and BD patients, but these studies make it difficult to address whether

these mechanisms are causally related to the pathogenesis of major psychosis. On the other hand,
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animal model studies of major psychosis and the translation of these studies into the clinic may help

overcome this challenge.

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Since major psychosis is a multifactorial and heterogeneous syndrome, the identification of subgroups
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has become more important for novel diagnostic markers and drug discoveries that can be used in the

diagnosis and treatment of patients with SZ and BD. While these drugs have to target syndrome-

specific pathophysiological changes, diagnostic markers have to give proper results that will definitely
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separate the subgroups. The most important questions likely to be addressed by new studies in this

context are whether epigenetic changes can be used to diagnose subtypes of major psychosis and
ur

whether epigenetic drugs can reduce SZ- and BD-related cognitive problems. Promisingly, studies on

abnormal gene expression in the postmortem brain and peripheral blood sample have revealed that
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epigenetic mechanisms may be viable tools for early diagnosis for some cases of SZ ve BD (Akbarian

and Huang, 2009; Fachim et al., 2019; Liu et al., 2017). However, there is limited research data to

examine the effects of DNMT and HDAC inhibitors in reducing cognitive deficits and the role of

antipsychotic drugs on epigenetic changes in the brain (Abel and Zukin, 2008; Bowden, 2007; Deutsch

et al., 2008; Dong et al., 2008). On the other hand, epigenetic evidence likely to be revealed by further

19
studies in this context seems very promising in the early diagnosis of SZ and BD subgroups and the

basis of the personalized treatment of major psychosis.

In conclusion, it is now known that epigenetic alterations play a role in normal brain functions and the

neuropathogenesis of SZ and BD in light of increasing evidence. These evidence are not only shedding

light on scientists in explaining the genetic, nongenetic heritable, and environmental factors that may

contribute to the molecular pathogenesis of major psychosis, but also promising for the identification

of new diagnostic protocols and therapeutic targets that can be used in the diagnosis and treatment of

SZ and BD. Moreover, epigenetics evidences elucidated by advanced studies may be form the basis of

of
"personalized” treatment in major psychosis.

Author’s contributions

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All the contributing authors have participated in preparation of the manuscript.

Funding
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This research did not receive any specific grant from funding agencies in the public, commercial, or

not-for-profit sectors
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Declaration of Competing Interest

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The authors have no conflict of interest with any commercial orother association in connection with

the submitted article

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ORCID

Çevik Gürel https://orcid.org/0000-0003-0266-2115

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Gökçe Ceren Kuşçu https://orcid.org/0000-0003-1750-8209

Altuğ Yavaşoğlu https://orcid.org/0000-0003-4227-1637

Çığır Biray Avcı https://orcid.org/0000-0001-8251-4520

20
References

Abdolmaleky, H.M., Cheng, K., Faraone, S. V., Wilcox, M., Glatt, S.J., Gao, F., Smith, C.L., Shafa,

R., Aeali, B., Carnevale, J., Pan, H., Papageorgis, P., Ponte, J.F., Sivaraman, V., Tsuang, M.T.,

Thiagalingam, S., 2006. Hypomethylation of MB-COMT promoter is a major risk factor for

schizophrenia and bipolar disorder. Hum. Mol. Genet. 15, 3132–3145.

https://doi.org/10.1093/hmg/ddl253

Abdolmaleky, H.M., Cheng, K.H., Russo, A., Smith, C.L., Faraone, S. V., Wilcox, M., Shafa, R.,

Glatt, S.J., Nguyen, G., Ponte, J.F., Thiagalingam, S., Tsuang, M.T., 2005. Hypermethylation of

of
the reelin (RELN) promoter in the brain of schizophrenic patients: A preliminary report. Am. J.

Med. Genet. - Neuropsychiatr. Genet. 134 B, 60–66. https://doi.org/10.1002/ajmg.b.30140

ro
Abdolmaleky, H.M., Pajouhanfar, S., Faghankhani, M., Joghataei, M.T., Mostafavi, A., Thiagalingam,
-p
S., 2015. Antipsychotic drugs attenuate aberrant DNA methylation of DTNBP1 (dysbindin)

promoter in saliva and post-mortem brain of patients with schizophrenia and Psychotic bipolar
re
disorder. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 168, 687–696.

https://doi.org/10.1002/ajmg.b.32361
lP

Abdolmaleky, H.M., Yaqubi, S., Papageorgis, P., Lambert, A.W., Ozturk, S., Sivaraman, V.,
na

Thiagalingam, S., 2011. Epigenetic dysregulation of HTR2A in the brain of patients with

schizophrenia and bipolar disorder. Schizophr. Res. 129, 183–190.

https://doi.org/10.1016/j.schres.2011.04.007
ur

Abel, T., Zukin, R.S., 2008. Epigenetic targets of HDAC inhibition in neurodegenerative and
Jo

psychiatric disorders. Curr. Opin. Pharmacol. 8, 57–64.

https://doi.org/10.1016/j.coph.2007.12.002

Akbarian, S., Huang, H.-S., 2009. Epigenetic regulation in human brain-focus on histone lysine

methylation. Biol. Psychiatry 65, 198–203. https://doi.org/10.1016/j.biopsych.2008.08.015

Akbarian, S., Ruehl, M.G., Bliven, E., Luiz, L.A., Peranelli, A.C., Baker, S.P., Roberts, R.C., Bunney,

21
 W.E., Conley, R.C., Jones, E.G., Tamminga, C.A., Guo, Y., 2005. Chromatin Alterations

Associated With Down-regulated Metabolic Gene Expression in the Prefrontal Cortex of

Subjects With Schizophrenia. Arch. Gen. Psychiatry 62, 829.

https://doi.org/10.1001/archpsyc.62.8.829

Alelú-Paz, R., González-Corpas, A., Ashour, N., Escanilla, A., Monje, A., Guerrero Márquez, C.,

Algora Weber, M., Ropero, S., 2015. DNA methylation pattern of gene promoters of major

neurotransmitter systems in older patients with schizophrenia with severe and mild cognitive

impairment. Int. J. Geriatr. Psychiatry 30, 558–565. https://doi.org/10.1002/gps.4182

of
An, J., Rao, A., Ko, M., 2017. TET family dioxygenases and DNA demethylation in stem cells and

cancers. Exp. Mol. Med. 49, e323. https://doi.org/10.1038/emm.2017.5

ro
Arechederra, M., Daian, F., Yim, A., Bazai, S.K., Richelme, S., Dono, R., Saurin, A.J., Habermann,
-p
B.H., Maina, F., 2018. Hypermethylation of gene body CpG islands predicts high dosage of

functional oncogenes in liver cancer. Nat. Commun. 9. https://doi.org/10.1038/s41467-018-

re
05550-5
lP

Autin, P., Blanquart, C., Fradin, D., 2019. Epigenetic Drugs for Cancer and microRNAs: A Focus on

Histone Deacetylase Inhibitors. Cancers (Basel). 11. https://doi.org/10.3390/cancers11101530

na

Azevedo, J.A., Carter, B.S., Meng, F., Turner, D.L., Dai, M., Schatzberg, A.F., Barchas, J.D., Jones,

E.G., Bunney, W.E., Myers, R.M., Akil, H., Watson, S.J., Thompson, R.C., 2016. The
ur

microRNA network is altered in anterior cingulate cortex of patients with unipolar and bipolar

depression. J. Psychiatr. Res. 82, 58–67. https://doi.org/10.1016/j.jpsychires.2016.07.012

Jo

Banigan, M.G., Kao, P.F., Kozubek, J.A., Winslow, A.R., Medina, J., Costa, J., Schmitt, A.,

Schneider, A., Cabral, H., Cagsal-Getkin, O., Vanderburg, C.R., Delalle, I., 2013. Differential

expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder

patients. PLoS One 8, e48814. https://doi.org/10.1371/journal.pone.0048814

Barry, G., Briggs, J.A., Vanichkina, D.P., Poth, E.M., Beveridge, N.J., Ratnu, V.S., Nayler, S.P.,

22
 Nones, K., Hu, J., Bredy, T.W., Nakagawa, S., Rigo, F., Taft, R.J., Cairns, M.J., Blackshaw, S.,

Wolvetang, E.J., Mattick, J.S., 2014. The long non-coding RNA Gomafu is acutely regulated in

response to neuronal activation and involved in schizophrenia-associated alternative splicing.

Mol. Psychiatry 19, 486–94. https://doi.org/10.1038/mp.2013.45

Batista, I. de A.A., Helguero, L.A., 2018. Biological processes and signal transduction pathways

regulated by the protein methyltransferase SETD7 and their significance in cancer. Signal

Transduct. Target. Ther. 3, 19. https://doi.org/10.1038/s41392-018-0017-6

Bavamian, S., Mellios, N., Lalonde, J., Fass, D.M., Wang, J., Sheridan, S.D., Madison, J.M., Zhou, F.,

of
Rueckert, E.H., Barker, D., Perlis, R.H., Sur, M., Haggarty, S.J., 2015. Dysregulation of miR-34a

links neuronal development to genetic risk factors for bipolar disorder. Mol. Psychiatry 20, 573–

ro
584. https://doi.org/10.1038/mp.2014.176

-p
Begolli, R., Sideris, N., Giakountis, A., 2019. LncRNAs as Chromatin Regulators in Cancer: From

Molecular Function to Clinical Potential. Cancers (Basel). 11.

re
https://doi.org/10.3390/cancers11101524
lP

Beveridge, N.J., Gardiner, E., Carroll, A.P., Tooney, P.A., Cairns, M.J., 2010. Schizophrenia is

associated with an increase in cortical microRNA biogenesis. Mol. Psychiatry 15, 1176–1189.
na

https://doi.org/10.1038/mp.2009.84

Bonnaud, E.M., Suberbielle, E., Malnou, C.E., 2016. Histone acetylation in neuronal (dys)function.
ur

Biomol. Concepts 7, 103–16. https://doi.org/10.1515/bmc-2016-0002

Borodinova, A.A., Kuznetsova, M.A., Alekseeva, V.S., Balaban, P.M., 2019. Histone acetylation
Jo

determines transcription of atypical protein kinases in rat neurons. Sci. Rep. 9, 4332.

https://doi.org/10.1038/s41598-019-40823-z

Bowden, C.L., 2007. Spectrum of effectiveness of valproate in neuropsychiatry. Expert Rev.

Neurother. 7, 9–16. https://doi.org/10.1586/14737175.7.1.9

Bromberg, A., Levine, J., Nemetz, B., Belmaker, R.H., Agam, G., 2008. No association between

23
 global leukocyte DNA methylation and homocysteine levels in schizophrenia patients.

Schizophr. Res. 101, 50–7. https://doi.org/10.1016/j.schres.2008.01.009

Burghardt, K.J., Howlett, B.H., Sanders, E., Dass, S.E., Msallaty, Z., Mallisho, A., Seyoum, B., Yi, Z.,

2019. Skeletal muscle DNA methylation modifications and psychopharmacologic treatment in

bipolar disorder. Eur. Neuropsychopharmacol. 29, 1365–1373.

https://doi.org/10.1016/j.euroneuro.2019.10.001

Cariaga-Martinez, A., Saiz-Ruiz, J., Alelú-Paz, R., 2016. From Linkage Studies to Epigenetics: What

We Know and What We Need to Know in the Neurobiology of Schizophrenia. Front. Neurosci.

of
10, 202. https://doi.org/10.3389/fnins.2016.00202

ro
Carrard, A., Salzmann, A., Malafosse, A., Karege, F., 2011. Increased DNA methylation status of the

serotonin receptor 5HTR1A gene promoter in schizophrenia and bipolar disorder. J. Affect.
-p
Disord. 132, 450–453. https://doi.org/10.1016/j.jad.2011.03.018
re
Chase, K.A., Gavin, D.P., Guidotti, A., Sharma, R.P., 2013. Histone methylation at H3K9: Evidence

for a restrictive epigenome in schizophrenia. Schizophr. Res. 149, 15–20.

lP

https://doi.org/10.1016/j.schres.2013.06.021

Chen, H.P., Zhao, Y.T., Zhao, T.C., 2015. Histone Deacetylases and Mechanisms of Regulation of
na

Gene Expression (Histone deacetylases in cancer). Crit. Rev. Oncog. 20, 35.

Chen, S., Yang, J., Wei, Y., Wei, X., 2019. Epigenetic regulation of macrophages: from homeostasis
ur

maintenance to host defense. Cell. Mol. Immunol. https://doi.org/10.1038/s41423-019-0315-0

Jo

Chen, X., Duan, H., Xiao, L., Gan, J., 2018. Genetic and Epigenetic Alterations Underlie

Oligodendroglia Susceptibility and White Matter Etiology in Psychiatric Disorders. Front. Genet.

9, 565. https://doi.org/10.3389/fgene.2018.00565

Chen, Y., Zhang, J., Zhang, L., Shen, Y., Xu, Q., 2012. Effects of MAOA promoter methylation on

susceptibility to paranoid schizophrenia. Hum. Genet. 131, 1081–1087.

https://doi.org/10.1007/s00439-011-1131-5

24
Chiechio, S., Zammataro, M., Morales, M.E., Busceti, C.L., Drago, F., Gereau, R.W., Copani, A.,

Nicoletti, F., 2009. Epigenetic Modulation of mGlu2 Receptors by Histone Deacetylase

Inhibitors in the Treatment of Inflammatory Pain. Mol. Pharmacol. 75, 1014–1020.

https://doi.org/10.1124/mol.108.054346

Choi, J.L., Kao, P.F., Itriago, E., Zhan, Y., Kozubek, J.A., Hoss, A.G., Banigan, M.G., Vanderburg,

C.R., Rezvani, A.H., Latourelle, J.C., Cabral, H., Delalle, I., 2017. miR-149 and miR-29c as

candidates for bipolar disorder biomarkers. Am. J. Med. Genet. Part B Neuropsychiatr. Genet.

174, 315–323. https://doi.org/10.1002/ajmg.b.32518

of
Christopher, M.A., Kyle, S.M., Katz, D.J., 2017. Neuroepigenetic mechanisms in disease. Epigenetics

Chromatin 10, 47. https://doi.org/10.1186/s13072-017-0150-4

ro
Chrun, E.S., Modolo, F., Daniel, F.I., 2017. Histone modifications: A review about the presence of
-p
this epigenetic phenomenon in carcinogenesis. Pathol. - Res. Pract. 213, 1329–1339.

https://doi.org/10.1016/j.prp.2017.06.013
re
Connor, C.M., Dincer, A., Straubhaar, J., Galler, J.R., Houston, I.B., Akbarian, S., 2012. Maternal
lP

immune activation alters behavior in adult offspring, with subtle changes in the cortical

transcriptome and epigenome. Schizophr. Res. 140, 175–184.

na

https://doi.org/10.1016/j.schres.2012.06.037

Çöpoğlu, Ü.S., Igci, M., Bozgeyik, E., Kokaçya, M.H., İğci, Y.Z., Dokuyucu, R., Ari, M., Savaş,
ur

H.A., 2016. DNA Methylation of BDNF Gene in Schizophrenia. Med. Sci. Monit. 22, 397–402.

Cruceanu, C., Alda, M., Nagy, C., Freemantle, E., Rouleau, G.A., Turecki, G., 2013. H3K4 tri-
Jo

methylation in synapsin genes leads to different expression patterns in bipolar disorder and major

depression. Int. J. Neuropsychopharmacol. 16, 289–99.

https://doi.org/10.1017/S1461145712000363

Dempster, E.L., Mill, J., Craig, I.W., Collier, D.A., 2006. The quantification of COMT mRNA in post

mortem cerebellum tissue: diagnosis, genotype, methylation and expression. BMC Med. Genet.

25
 7, 10. https://doi.org/10.1186/1471-2350-7-10

Deutsch, S.I., Rosse, R.B., Mastropaolo, J., Long, K.D., Gaskins, B.L., 2008. Epigenetic therapeutic

strategies for the treatment of neuropsychiatric disorders: ready for prime time? Clin.

Neuropharmacol. 31, 119. https://doi.org/10.1097/WNF.0b013e318067e255

Dong, E., Agis-Balboa, R.C., Simonini, M. V, Grayson, D.R., Costa, E., Guidotti, A., 2005. Reelin

and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced

mouse model of schizophrenia. Proc. Natl. Acad. Sci. U. S. A. 102, 12578–83.

https://doi.org/10.1073/pnas.0505394102

of
Dong, E., Gavin, D.P., Chen, Y., Davis, J., 2012. Upregulation of TET1 and downregulation of

ro
APOBEC3A and APOBEC3C in the parietal cortex of psychotic patients. Transl. Psychiatry 2.

https://doi.org/10.1038/tp.2012.86
-p
Dong, E., Nelson, M., Grayson, D.R., Costa, E., Guidotti, A., 2008. Clozapine and sulpiride but not
re
haloperidol or olanzapine activate brain DNA demethylation. Proc. Natl. Acad. Sci. 105, 13614–

13619. https://doi.org/10.1073/pnas.0805493105
lP

Duan, J., Sanders, A.R., Gejman, P. V, 2019. From Schizophrenia Genetics to Disease Biology:

Harnessing New Concepts and Technologies. J. psychiatry brain Sci. 4.

na

https://doi.org/10.20900/jpbs.20190014

Duffy, A., Goodday, S.M., Keown-Stoneman, C., Scotti, M., Maitra, M., Nagy, C., Horrocks, J.,
ur

Turecki, G., 2019. Epigenetic markers in inflammation-related genes associated with mood

disorder: a cross-sectional and longitudinal study in high-risk offspring of bipolar parents. Int. J.
Jo

Bipolar Disord. 7, 17. https://doi.org/10.1186/s40345-019-0152-1

Fachim, H.A., Loureiro, C.M., Corsi-Zuelli, F., Shuhama, R., Louzada-Junior, P., Menezes, P.R.,

Dalton, C.F., Del-Ben, C.M., Reynolds, G.P., 2019. GRIN2B promoter methylation deficits in

early-onset schizophrenia and its association with cognitive function. Epigenomics 11, 401–410.

https://doi.org/10.2217/epi-2018-0127

26
Fallah, H., Azari, I., Neishabouri, S.M., Oskooei, V.K., Taheri, M., Ghafouri-Fard, S., 2019. Sex-

specific up-regulation of lncRNAs in peripheral blood of patients with schizophrenia. Sci. Rep.

9. https://doi.org/10.1038/s41598-019-49265-z

Fang, Y., Qiu, Q., Zhang, S., Sun, L., Li, G., Xiao, S., Li, X., 2018. Changes in miRNA-132 and miR-

124 levels in non-treated and citalopram-treated patients with depression. J. Affect. Disord. 227,

745–751. https://doi.org/10.1016/j.jad.2017.11.090

Föcking, M., Doyle, B., Munawar, N., Dillon, E.T., Cotter, D., Cagney, G., 2019. Epigenetic Factors

in Schizophrenia: Mechanisms and Experimental Approaches. Mol. Neuropsychiatry 5, 6–12.

of
https://doi.org/10.1159/000495063

ro
Gao, J., Yi, H., Tang, X., Feng, X., Yu, M., Sha, W., Wang, X., Zhang, Xiaobin, Zhang, Xiangrong,

2018. DNA Methylation and Gene Expression of Matrix Metalloproteinase 9 Gene in Deficit and
-p
Non-deficit Schizophrenia. Front. Genet. 9, 646. https://doi.org/10.3389/fgene.2018.00646
re
Garcia-Ruiz, B., Moreno, L., Muntané, G., Sánchez-Gistau, V., Gutiérrez-Zotes, A., Martorell, L.,

Labad, J., Vilella, E., 2020. Leukocyte and brain DDR1 hypermethylation is altered in psychosis
lP

and is correlated with stress and inflammatory markers . Epigenomics.

https://doi.org/10.2217/epi-2019-0191
na

Gavin, D.P., Rosen, C., Chase, K., Grayson, D.R., Tun, N., Sharma, R.P., 2009. Dimethylated lysine 9

of histone 3 is elevated in schizophrenia and exhibits a divergent response to histone deacetylase

ur

inhibitors in lymphocyte cultures. J. Psychiatry Neurosci. 34, 232–237.

George, V.C., Ansari, S.A., Chelakkot, V.S., Chelakkot, A.L., Chelakkot, C., Menon, V., Ramadan,
Jo

W., Ethiraj, K.R., El-Awady, R., Mantso, T., Mitsiogianni, M., Panagiotidis, M.I., Dellaire, G.,

Vasantha Rupasinghe, H.P., 2019. DNA-dependent protein kinase: Epigenetic alterations and the

role in genomic stability of cancer. Mutat. Res. Mutat. Res. 780, 92–105.

https://doi.org/10.1016/j.mrrev.2018.06.001

Gescher, D.M., Kahl, K.G., Hillemacher, T., Frieling, H., Kuhn, J., Frodl, T., 2018. Epigenetics in

27
 Personality Disorders: Today’s Insights. Front. Psychiatry 9, 579.

https://doi.org/10.3389/fpsyt.2018.00579

Gibbons, A., Udawela, M., Dean, B., 2018. Non-Coding RNA as Novel Players in the

Pathophysiology of Schizophrenia. Non-coding RNA 4, 11.

https://doi.org/10.3390/ncrna4020011

Girdhar, K., Hoffman, G.E., Jiang, Y., Brown, L., Kundakovic, M., Hauberg, M.E., Francoeur, N.J.,

Wang, Y. chih, Shah, H., Kavanagh, D.H., Zharovsky, E., Jacobov, R., Wiseman, J.R., Park, R.,

Johnson, J.S., Kassim, B.S., Sloofman, L., Mattei, E., Weng, Z., Sieberts, S.K., Peters, M.A.,

of
Harris, B.T., Lipska, B.K., Sklar, P., Roussos, P., Akbarian, S., 2018. Cell-specific histone

modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome.

ro
Nat. Neurosci. 21, 1126–1136. https://doi.org/10.1038/s41593-018-0187-0

-p
Grayson, D.R., Guidotti, A., 2013. The Dynamics of DNA Methylation in Schizophrenia and Related

Psychiatric Disorders. Neuropsychopharmacology 38, 138–166.

re
https://doi.org/10.1038/npp.2012.125
lP

Grayson, D.R., Jia, X., Chen, Y., Sharma, R.P., Mitchell, C.P., Guidotti, A., Costa, E., 2005. Reelin

promoter hypermethylation in schizophrenia. Proc. Natl. Acad. Sci. U. S. A. 102, 9341–9346.

na

https://doi.org/10.1073/pnas.0503736102

Greenberg, M.V.C., Bourc’his, D., 2019. The diverse roles of DNA methylation in mammalian
ur

development and disease. Nat. Rev. Mol. Cell Biol. 20, 590–607. https://doi.org/10.1038/s41580-

019-0159-6
Jo

Guidotti, A., Ruzicka, W., Grayson, D.R., Veldic, M., Pinna, G., Davis, J.M., Costa, E., 2007. S-

adenosyl methionine and DNA methyltransferase-1 mRNA overexpression in psychosis.

Neuroreport 18, 57–60. https://doi.org/10.1097/WNR.0b013e32800fefd7

Hałasa, M., Wawruszak, A., Przybyszewska, A., Jaruga, A., Guz, M., Kałafut, J., Stepulak, A.,

Cybulski, M., 2019. H3K18Ac as a Marker of Cancer Progression and Potential Target of Anti-

28
 Cancer Therapy. Cells 8, 485. https://doi.org/10.3390/cells8050485

Henning, A.N., Roychoudhuri, R., Restifo, N.P., 2018. Epigenetic control of CD8+ T cell

differentiation. Nat. Rev. Immunol. 18, 340–356. https://doi.org/10.1038/nri.2017.146

Hoffman, G.E., Bendl, J., Voloudakis, G., Montgomery, K.S., Sloofman, L., Wang, Y.-C., Shah, H.R.,

Hauberg, M.E., Johnson, J.S., Girdhar, K., Song, L., Fullard, J.F., Kramer, R., Hahn, C.-G., Gur,

R., Marenco, S., Lipska, B.K., Lewis, D.A., Haroutunian, V., Hemby, S., Sullivan, P., Akbarian,

S., Chess, A., Buxbaum, J.D., Crawford, G.E., Domenici, E., Devlin, B., Sieberts, S.K., Peters,

M.A., Roussos, P., 2019. CommonMind Consortium provides transcriptomic and epigenomic

of
data for Schizophrenia and Bipolar Disorder. Sci. data 6, 180. https://doi.org/10.1038/s41597-

019-0183-6

ro
Hsieh, M.-T., Lin, C.-C., Huang, T.-L., 2019. Increased brain-derived neurotrophic factor exon IV
-p
histone 3 lysine 9 dimethylation in patients with schizophrenia. Taiwan. J. Psychiatry 33, 104.

https://doi.org/10.4103/tpsy.tpsy_18_19
re
Hu, T.-M., Chen, S.-J., Hsu, S.-H., Cheng, M.-C., 2019. Functional analyses and effect of DNA
lP

methylation on the EGR1 gene in patients with schizophrenia. Psychiatry Res. 275, 276–282.

https://doi.org/10.1016/j.psychres.2019.03.044
na

Huang, H.-S., Matevossian, A., Whittle, C., Kim, S.Y., Schumacher, A., Baker, S.P., Akbarian, S.,

2007. Prefrontal Dysfunction in Schizophrenia Involves Mixed-Lineage Leukemia 1-Regulated

ur

Histone Methylation at GABAergic Gene Promoters. J. Neurosci. 27, 11254–11262.

https://doi.org/10.1523/JNEUROSCI.3272-07.2007
Jo

Hyman, S.E., 2012. Target practice: HDAC inhibitors for schizophrenia. Nat. Neurosci. 15, 1180–1.

https://doi.org/10.1038/nn.3200

Ibi, D., Fujiki, Y., Koide, N., Nakasai, G., Takaba, R., Hiramatsu, M., 2019. Paternal valproic acid

exposure in mice triggers behavioral alterations in offspring. Neurotoxicol. Teratol. 76.

https://doi.org/10.1016/j.ntt.2019.106837

29
Jambhekar, A., Dhall, A., Shi, Y., 2019. Roles and regulation of histone methylation in animal

development. Nat. Rev. Mol. Cell Biol. 20, 625–641. https://doi.org/10.1038/s41580-019-0151-1

Javaid, N., Choi, S., 2017. Acetylation- and Methylation-Related Epigenetic Proteins in the Context of

Their Targets. Genes (Basel). 8. https://doi.org/10.3390/genes8080196

Jiang, T., Zong, L., Zhou, L., Hou, Y., Zhang, L., Zheng, X., Han, H., Li, S., Zhang, W., Zhang, J.,

Deng, C., Jia, Y., Zhao, C., 2017. Variation in global DNA hydroxymethylation with age

associated with schizophrenia. Psychiatry Res. 257, 497–500.

https://doi.org/10.1016/j.psychres.2017.08.022

of
Jobe, E.M., Zhao, X., 2016. DNA Methylation and Adult Neurogenesis. Brain Plast. 3, 5–26.

ro
https://doi.org/10.3233/bpl-160034

Ju, H., Zhang, L., Mao, L., Wu, Y., Liu, S., Ruan, M., Hu, J., Ren, G., 2018. A comprehensive
-p
genome-wide analysis of the long noncoding RNA expression profile in metastatic lymph nodes
re
of oral mucosal melanoma. Gene 675, 44–53. https://doi.org/10.1016/j.gene.2018.06.064

Kaminsky, Z., Jones, I., Verma, R., Saleh, L., Trivedi, H., Guintivano, J., Akman, R., Zandi, P., Lee,
lP

R.S., Potash, J.B., 2015. DNA methylation and expression of KCNQ3 in bipolar disorder.

Bipolar Disord. 17, 150–159. https://doi.org/10.1111/bdi.12230

na

Kano, S., Colantuoni, C., Han, F., Zhou, Z., Yuan, Q., Wilson, A., Takayanagi, Y., Lee, Y., Rapoport,

J., Eaton, W., Cascella, N., Ji, H., Goldman, D., Sawa, A., 2013. Genome-wide profiling of
ur

multiple histone methylations in olfactory cells: further implications for cellular susceptibility to

oxidative stress in schizophrenia. Mol. Psychiatry 18, 740–2.

Jo

https://doi.org/10.1038/mp.2012.120

Kim, A.H., Reimers, M., Maher, B., Williamson, V., McMichael, O., McClay, J.L., van den Oord,

E.J.C.G., Riley, B.P., Kendler, K.S., Vladimirov, V.I., 2010. MicroRNA expression profiling in

the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders. Schizophr.

Res. 124, 183–191. https://doi.org/10.1016/j.schres.2010.07.002

30
Kim, H.J., Eoh, K.J., Kim, L.K., Nam, E.J., Yoon, S.O., Kim, K.-H., Lee, J.K., Kim, S.W., Kim, Y.T.,

2016. The long noncoding RNA &lt;i&gt;HOXA11 antisense&lt;/i&gt; induces tumor

progression and stemness maintenance in cervical cancer. Oncotarget 7, 83001–83016.

https://doi.org/10.18632/oncotarget.12863

Kocerha, J., Dwivedi, Y., Brennand, K.J., 2015. Noncoding RNAs and neurobehavioral mechanisms

in psychiatric disease. Mol. Psychiatry 20, 677–684. https://doi.org/10.1038/mp.2015.30

Kuehner, J.N., Bruggeman, E.C., Wen, Z., Yao, B., 2019. Epigenetic Regulations in Neuropsychiatric

Disorders. Front. Genet. 10, 268. https://doi.org/10.3389/fgene.2019.00268

of
Kurita, M., Holloway, T., García-Bea, A., Kozlenkov, A., Friedman, A.K., Moreno, J.L., Heshmati,

ro
M., Golden, S.A., Kennedy, P.J., Takahashi, N., Dietz, D.M., Mocci, G., Gabilondo, A.M.,

Hanks, J., Umali, A., Callado, L.F., Gallitano, A.L., Neve, R.L., Shen, L., Buxbaum, J.D., Han,
-p
M.-H., Nestler, E.J., Meana, J.J., Russo, S.J., González-Maeso, J., 2012. HDAC2 regulates

atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nat.
re
Neurosci. 15, 1245–1254. https://doi.org/10.1038/nn.3181
lP

Kuswanto, C.N., Sum, M.Y., Qiu, A., Sitoh, Y.-Y., Liu, J., Sim, K., 2015. The impact of genome wide

supported microRNA-137 (MIR137) risk variants on frontal and striatal white matter integrity,
na

neurocognitive functioning, and negative symptoms in schizophrenia. Am. J. Med. Genet. B.

Neuropsychiatr. Genet. 168B, 317–26. https://doi.org/10.1002/ajmg.b.32314

ur

Lai, C.-Y., Lee, S.-Y., Scarr, E., Yu, Y.-H., Lin, Y.-T., Liu, C.-M., Hwang, T.-J., Hsieh, M.H., Liu,

C.-C., Chien, Y.-L., Udawela, M., Gibbons, A.S., Everall, I.P., Hwu, H.-G., Dean, B., Chen,
Jo

W.J., 2016. Aberrant expression of microRNAs as biomarker for schizophrenia: from acute state

to partial remission, and from peripheral blood to cortical tissue. Transl. Psychiatry 6, e717–

e717. https://doi.org/10.1038/tp.2015.213

Lee, G.H., D’Arcangelo, G., 2016. New Insights into Reelin-Mediated Signaling Pathways. Front.

Cell. Neurosci. 10, 122. https://doi.org/10.3389/fncel.2016.00122

31
Li, Y., Li, Z., Dong, L., Tang, M., Zhang, P., Zhang, C., Cao, Z., Zhu, Q., Chen, Y., Wang, Hui,

Wang, T., Lv, D., Wang, L., Zhao, Y., Yang, Y., Wang, Haiying, Zhang, H., Roeder, R.G., Zhu,

W.-G., 2018. Histone H1 acetylation at lysine 85 regulates chromatin condensation and genome

stability upon DNA damage. Nucleic Acids Res. 46, 7716–7730.

https://doi.org/10.1093/nar/gky568

Liu, S., Zhang, F., Shugart, Y.Y., Yang, L., Li, X., Liu, Z., Sun, N., Yang, C., Guo, X., Shi, J., Wang,

L., Cheng, L., Zhang, K., Yang, T., Xu, Y., 2017. The early growth response protein 1-miR-30a-

5p-neurogenic differentiation factor 1 axis as a novel biomarker for schizophrenia diagnosis and

of
treatment monitoring. Transl. Psychiatry 7, e998–e998. https://doi.org/10.1038/tp.2016.268

Lu, Q., Wu, R., Zhao, M., Garcia-Gomez, A., Ballestar, E., 2019. miRNAs as Therapeutic Targets in

ro
Inflammatory Disease. Trends Pharmacol. Sci. https://doi.org/10.1016/j.tips.2019.09.007

-p
Luykx, J., Giuliani, F., Veldink, J., Kahn, R., 2017. RNA sequencing in bipolar disorder: from long

non-coding to circular rnas. Eur. Psychiatry 41, S56.

re
https://doi.org/10.1016/j.eurpsy.2017.01.036
lP

Lyko, F., 2017. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat.

Rev. Genet. 19, 81–92. https://doi.org/10.1038/nrg.2017.80

na

Maćkowiak, M., Bator, E., Latusz, J., Mordalska, P., Wedzony, K., 2014. Prenatal MAM

administration affects histone H3 methylation in postnatal life in the rat medial prefrontal cortex.
ur

Eur. Neuropsychopharmacol. 24, 271–289. https://doi.org/10.1016/j.euroneuro.2013.05.013

Magri, C., Giacopuzzi, E., La Via, L., Bonini, D., Ravasio, V., Elhussiny, M.E.A., Orizio, F.,
Jo

Gangemi, F., Valsecchi, P., Bresciani, R., Barbon, A., Vita, A., Gennarelli, M., 2018. A novel

homozygous mutation in GAD1 gene described in a schizophrenic patient impairs activity and

dimerization of GAD67 enzyme. Sci. Rep. 8, 15470. https://doi.org/10.1038/s41598-018-33924-

Matrisciano, F., Panaccione, I., Grayson, D.R., Nicoletti, F., Guidotti, A., 2016. Metabotropic

32
 Glutamate 2/3 Receptors and Epigenetic Modifications in Psychotic Disorders: A Review. Curr.

Neuropharmacol. 14, 41–7. https://doi.org/10.2174/1570159X13666150713174242

McGowan, P.O., Kato, T., 2008. Epigenetics in mood disorders. Environ. Health Prev. Med.

https://doi.org/10.1007/s12199-007-0002-0

Mendizabal, I., Berto, S., Usui, N., Toriumi, K., Chatterjee, P., Douglas, C., Huh, I., Jeong, H.,

Layman, T., Tamminga, C.A., Preuss, T.M., Konopka, G., Yi, S. V, 2019. Cell type-specific

epigenetic links to schizophrenia risk in the brain. Genome Biol. 20, 135.

https://doi.org/10.1186/s13059-019-1747-7

of
Mill, J., Tang, T., Kaminsky, Z., Khare, T., Yazdanpanah, S., Bouchard, L., Jia, P., Assadzadeh, A.,

ro
Flanagan, J., Schumacher, A., Wang, S.-C., Petronis, A., 2008. Epigenomic Profiling Reveals

DNA-Methylation Changes Associated with Major Psychosis. Am. J. Hum. Genet. 82, 696–711.

https://doi.org/10.1016/j.ajhg.2008.01.008
-p
re
Monaghan, L., Massett, M.E., Bunschoten, R.P., Hoose, A., Pirvan, P.-A., Liskamp, R.M.J.,

Jørgensen, H.G., Huang, X., 2019. The Emerging Role of H3K9me3 as a Potential Therapeutic
lP

Target in Acute Myeloid Leukemia. Front. Oncol. 9, 705.

https://doi.org/10.3389/fonc.2019.00705
na

Moreau, M.P., Bruse, S.E., David-Rus, R., Buyske, S., Brzustowicz, L.M., 2011. Altered MicroRNA

Expression Profiles in Postmortem Brain Samples from Individuals with Schizophrenia and
ur

Bipolar Disorder. Biol. Psychiatry 69, 188–193. https://doi.org/10.1016/j.biopsych.2010.09.039

Naghavi-Gargari, B., Zahirodin, A., Ghaderian, S.M.H., Shirvani-Farsani, Z., 2019. Significant
Jo

increasing of DISC2 long non-coding RNA expression as a potential biomarker in bipolar

disorder. Neurosci. Lett. 696, 206–211. https://doi.org/10.1016/j.neulet.2018.12.044

Narahari, A., Hussain, M., Sreeram, V., 2017. MicroRNAs as Biomarkers for Psychiatric Conditions:

A Review of Current Research. Innov. Clin. Neurosci. 14, 53–55.

Nestler, E.J., Peña, C.J., Kundakovic, M., Mitchell, A., Akbarian, S., 2016. Epigenetic Basis of Mental

33
 Illness. Neurosci. 22, 447–463. https://doi.org/10.1177/1073858415608147

Ni, C., Jiang, W., Wang, Zhongju, Wang, Zhuo, Zhang, J., Zheng, X., Liu, Z., Ou, H., Jiang, T., Liang,

W., Wu, F., Li, Q., Hou, Y., Yang, Q., Guo, B., Liu, S., Li, Shuyun, Li, Shufen, Yang, E., Zhu,

X.-H., Huang, X., Wen, Z., Zhao, C., 2020. LncRNA-AC006129.1 reactivates a SOCS3-

mediated anti-inflammatory response through DNA methylation-mediated CIC downregulation

in schizophrenia. Mol. Psychiatry 1–18. https://doi.org/10.1038/s41380-020-0662-3

Nohesara, S., Ghadirivasfi, M., Mostafavi, S., Eskandari, M.R., Ahmadkhaniha, H.R., Thiagalingam,

S., Abdolmaleky, H.M., 2011. DNA hypomethylation of MB-COMT promoter in the DNA

of
derived from saliva in schizophrenia and bipolar disorder. J. Psychiatr. Res. 45, 1432–1438.

https://doi.org/10.1016/j.jpsychires.2011.06.013

ro
Ovenden, E.S., McGregor, N.W., Emsley, R.A., Warnich, L., 2018. DNA methylation and
-p
antipsychotic treatment mechanisms in schizophrenia: Progress and future directions. Prog.

Neuro-Psychopharmacology Biol. Psychiatry 81, 38–49.

re
https://doi.org/10.1016/j.pnpbp.2017.10.004
lP

Pai, S., Li, P., Killinger, B., Marshall, L., Jia, P., Liao, J., Petronis, A., Szabó, P.E., Labrie, V., 2019.

Differential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in

na

major psychosis. Nat. Commun. 10. https://doi.org/10.1038/s41467-019-09786-7

Pal, M., Ebrahimi, S., Oh, G., Khare, T., Zhang, A., Kaminsky, Z.A., Wang, S.-C., Petronis, A., 2015.
ur

High Precision DNA Modification Analysis of HCG9 in Major Psychosis. Schizophr. Bull. 42,

sbv079. https://doi.org/10.1093/schbul/sbv079
Jo

Perkins, D.O., Jeffries, C.D., Jarskog, L.F., Thomson, J.M., Woods, K., Newman, M.A., Parker, J.S.,

Jin, J., Hammond, S.M., 2007. microRNA expression in the prefrontal cortex of individuals with

schizophrenia and schizoaffective disorder. Genome Biol. 8, R27. https://doi.org/10.1186/gb-

2007-8-2-r27

Peter, C.J., Akbarian, S., 2011. Balancing histone methylation activities in psychiatric disorders.

34
 Trends Mol. Med. 17, 372–9. https://doi.org/10.1016/j.molmed.2011.02.003

Pfeifer, G.P., 2018. Defining driver DNA methylation changes in human cancer. Int. J. Mol. Sci.

https://doi.org/10.3390/ijms19041166

Polesskaya, O.O., Haroutunian, V., Davis, K.L., Hernandez, I., Sokolov, B.P., 2003. Novel putative

nonprotein-coding RNA gene from 11q14 displays decreased expression in brains of patients

with schizophrenia. J. Neurosci. Res. 74, 111–122. https://doi.org/10.1002/jnr.10752

Popendikyte, V., Laurinavicius, A., Paterson, A.D., Macciardi, F., Kennedy, J.L., Petronis, A., 1999.

of
DNA methylation at the putative promoter region of the human dopamine D2 receptor gene.

Neuroreport 10, 1249–1255. https://doi.org/10.1097/00001756-199904260-00018

ro
Qi, C., Xu, C.-J., Koppelman, G.H., 2019. The role of epigenetics in the development of childhood

asthma. Expert Rev. Clin. Immunol. https://doi.org/10.1080/1744666X.2020.1686977

-p
Qin, J., Wen, B., Liang, Y., Yu, W., Li, H., 2019. Histone Modifications and their Role in Colorectal
re
Cancer (Review). Pathol. Oncol. Res. https://doi.org/10.1007/s12253-019-00663-8
lP

Quintanal-Villalonga, Á., Molina-Pinelo, S., 2019. Epigenetics of lung cancer: a translational

perspective. Cell. Oncol. https://doi.org/10.1007/s13402-019-00465-9

na

Rao, J.S., Keleshian, V.L., Klein, S., Rapoport, S.I., 2012. Epigenetic modifications in frontal cortex

from Alzheimer’s disease and bipolar disorder patients. Transl. Psychiatry 2, e132–e132.

https://doi.org/10.1038/tp.2012.55
ur

Rao, S.-Q., Hu, H.-L., Ye, N., Shen, Y., Xu, Q., 2015. Genetic variants in long non-coding RNA
Jo

MIAT contribute to risk of paranoid schizophrenia in a Chinese Han population. Schizophr. Res.

166, 125–130. https://doi.org/10.1016/j.schres.2015.04.032

Rasmussen, K.D., Helin, K., 2016. Role of TET enzymes in DNA methylation, development, and

cancer. Genes Dev. 30, 733–750. https://doi.org/10.1101/gad.276568.115

Ren, Y., Cui, Y., Li, X., Wang, B., Na, L., Shi, J., Wang, L., Qiu, L., Zhang, K., Liu, G., Xu, Y., 2015.

35
 A co-expression network analysis reveals lncRNA abnormalities in peripheral blood in early-

onset schizophrenia. Prog. Neuro-Psychopharmacology Biol. Psychiatry 63, 1–5.

https://doi.org/10.1016/j.pnpbp.2015.05.002

Roth, T.L., Lubin, F.D., Sodhi, M., Kleinman, J.E., 2009. Epigenetic mechanisms in schizophrenia.

Biochim. Biophys. Acta - Gen. Subj. 1790, 869–877.

https://doi.org/10.1016/j.bbagen.2009.06.009

Sayad, A., Taheri, M., Omrani, M.D., Fallah, H., Kholghi Oskooei, V., Ghafouri-Fard, S., 2019.

Peripheral expression of long non-coding RNAs in bipolar patients. J. Affect. Disord. 249, 169–

of
174. https://doi.org/10.1016/J.JAD.2019.02.034

ro
Setten, R.L., Rossi, J.J., Han, S., 2019. The current state and future directions of RNAi-based

therapeutics. Nat. Rev. Drug Discov. https://doi.org/10.1038/s41573-019-0017-4

-p
Shanmugam, M.K., Arfuso, F., Arumugam, S., Chinnathambi, A., Jinsong, B., Warrier, S., Wang,
re
L.Z., Kumar, A.P., Ahn, K.S., Sethi, G., Lakshmanan, M., 2018. Role of novel histone

modifications in cancer. Oncotarget 9, 11414–11426. https://doi.org/10.18632/oncotarget.23356

lP

Sharma, R.P., Feiner, B., Chase, K.A., 2015. Histone H3 phosphorylation is upregulated in PBMCs of

schizophrenia patients in comparison to healthy controls. Schizophr. Res. 169, 498.

na

https://doi.org/10.1016/J.SCHRES.2015.09.030

Sharma, R.P., Grayson, D.R., Gavin, D.P., 2008. Histone deactylase 1 expression is increased in the
ur

prefrontal cortex of schizophrenia subjects: Analysis of the National Brain Databank microarray

collection. Schizophr. Res. 98, 111–117. https://doi.org/10.1016/j.schres.2007.09.020

Jo

Shinozaki, G., Hing, B., Potash, J.B., 2014. Epigenetics of Bipolar Disorder, in: Epigenetics in

Psychiatry. Elsevier Inc., pp. 265–278. https://doi.org/10.1016/B978-0-12-417114-5.00013-9

Singh, A., Gupta, S., Sachan, M., 2019. Epigenetic Biomarkers in the Management of Ovarian Cancer:

Current Prospectives. Front. cell Dev. Biol. 7, 182. https://doi.org/10.3389/fcell.2019.00182

36
Snyder, M.A., Gao, W.-J., 2019. NMDA receptor hypofunction for schizophrenia revisited:

Perspectives from epigenetic mechanisms. Schizophr. Res.

https://doi.org/10.1016/j.schres.2019.03.010

Starnawska, A., Demontis, D., McQuillin, A., O’Brien, N.L., Staunstrup, N.H., Mors, O., Nielsen,

A.L., Børglum, A.D., Nyegaard, M., 2016. Hypomethylation of FAM63B in bipolar disorder

patients. Clin. Epigenetics 8, 52. https://doi.org/10.1186/s13148-016-0221-6

Steardo, L., de Filippis, R., Carbone, E.A., Segura-Garcia, C., Verkhratsky, A., De Fazio, P., Fazio, P.

De, 2019. Sleep Disturbance in Bipolar Disorder: Neuroglia and Circadian Rhythms. Front.

of
psychiatry 10, 501. https://doi.org/10.3389/fpsyt.2019.00501

ro
Strazisar, M., Cammaerts, S., van der Ven, K., Forero, D.A., Lenaerts, A.-S., Nordin, A., Almeida-

Souza, L., Genovese, G., Timmerman, V., Liekens, A., De Rijk, P., Adolfsson, R., Callaerts, P.,
-p
Del-Favero, J., 2015. MIR137 variants identified in psychiatric patients affect synaptogenesis

and neuronal transmission gene sets. Mol. Psychiatry 20, 472–481.

re
https://doi.org/10.1038/mp.2014.53
lP

Sugawara, H., Murata, Y., Ikegame, T., Sawamura, R., Shimanaga, S., Takeoka, Y., Saito, T., Ikeda,

M., Yoshikawa, A., Nishimura, F., Kawamura, Y., Kakiuchi, C., Sasaki, T., Iwata, N.,
na

Hashimoto, M., Kasai, K., Kato, T., Bundo, M., Iwamoto, K., 2018. DNA methylation analyses

of the candidate genes identified by a methylome-wide association study revealed common

epigenetic alterations in schizophrenia and bipolar disorder. Psychiatry Clin. Neurosci. 72, 245–
ur

254. https://doi.org/10.1111/pcn.12645
Jo

Sun, J., Wang, C., 2019. Long non-coding RNAs in cardiac hypertrophy. Heart Fail. Rev.

https://doi.org/10.1007/s10741-019-09882-2

Tamura, Y., Kunugi, H., Ohashi, J., Hohjoh, H., 2007. Epigenetic aberration of the human REELIN

gene in psychiatric disorders. Mol. Psychiatry 12, 519, 593–600.

https://doi.org/10.1038/sj.mp.4002014

37
Tang, B., Dean, B., Thomas, E.A., 2011. Disease- and age-related changes in histone acetylation at

gene promoters in psychiatric disorders. Transl. Psychiatry 1, e64–e64.

https://doi.org/10.1038/tp.2011.61

Tang, B., Jia, H., Kast, R.J., Thomas, E.A., 2013. Epigenetic changes at gene promoters in response to

immune activation in utero. Brain. Behav. Immun. 30, 168–175.

https://doi.org/10.1016/j.bbi.2013.01.086

Tochigi, M., Iwamoto, K., Bundo, M., Komori, A., Sasaki, T., Kato, N., Kato, T., 2008. Methylation

status of the reelin promoter region in the brain of schizophrenic patients. Biol. Psychiatry 63,

of
530–3. https://doi.org/10.1016/j.biopsych.2007.07.003

ro
Tolosa, A., Sanjuán, J., Dagnall, A.M., Moltó, M.D., Herrero, N., de Frutos, R., 2010. FOXP2 gene

and language impairment in schizophrenia: association and epigenetic studies. BMC Med. Genet.

11, 114. https://doi.org/10.1186/1471-2350-11-114

-p
re
Tremolizzo, L., Carboni, G., Ruzicka, W.B., Mitchell, C.P., Sugaya, I., Tueting, P., Sharma, R.,

Grayson, D.R., Costa, E., Guidotti, A., 2002. An epigenetic mouse model for molecular and
lP

behavioral neuropathologies related to schizophrenia vulnerability. Proc. Natl. Acad. Sci. U. S.

A. 99, 17095–100. https://doi.org/10.1073/pnas.262658999

na

Veldic, M., Caruncho, H.J., Liu, W.S., Davis, J., Satta, R., Grayson, D.R., Guidotti, A., Costa, E.,

2004. DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic

ur

interneurons of schizophrenia brains. Proc. Natl. Acad. Sci. 101, 348–353.

https://doi.org/10.1073/pnas.2637013100
Jo

von Knethen, A., Brüne, B., 2019. Histone Deacetylation Inhibitors as Therapy Concept in Sepsis. Int.

J. Mol. Sci. 20. https://doi.org/10.3390/ijms20020346

Walton, E., Liu, J., Hass, J., White, T., Scholz, M., Roessner, V., Gollub, R., Calhoun, V.D., Ehrlich,

S., 2014. MB-COMT promoter DNA methylation is associated with working-memory processing

in schizophrenia patients and healthy controls. Epigenetics 9, 1101–1107.

38
 https://doi.org/10.4161/epi.29223

Wang, T., Gao, H., Li, W., Liu, C., 2019. Essential Role of Histone Replacement and Modifications in

Male Fertility. Front. Genet. 10. https://doi.org/10.3389/fgene.2019.00962

Wang, Z., Tang, B., He, Y., Jin, P., 2016. DNA methylation dynamics in neurogenesis. Epigenomics

8, 401–414. https://doi.org/10.2217/epi.15.119

Wei, H., Yuan, Y., Liu, S., Wang, Cheng, Yang, F., Lu, Z., Wang, Chuanyue, Deng, H., Zhao, J.,

Shen, Y., Zhang, C., Yu, X., Xu, Q., 2015. Detection of Circulating miRNA Levels in

of
Schizophrenia. Am. J. Psychiatry 172, 1141–1147.

https://doi.org/10.1176/appi.ajp.2015.14030273

ro
Wockner, L.F., Noble, E.P., Lawford, B.R., Young, R.M., Morris, C.P., Whitehall, V.L.J., Voisey, J.,

2014. Genome-wide DNA methylation analysis of human brain tissue from schizophrenia
-p
patients. Transl. Psychiatry 4, e339–e339. https://doi.org/10.1038/tp.2013.111
re
Wróblewski, A., Strycharz, J., Świderska, E., Drewniak, K., Drzewoski, J., Szemraj, J., Kasznicki, J.,

Śliwińska, A., 2019. Molecular Insight into the Interaction between Epigenetics and Leptin in
lP

Metabolic Disorders. Nutrients 11, 1872. https://doi.org/10.3390/nu11081872

Yan, N., Mu, K., An, X.F., Li, L., Qin, Q., Song, R.H., Yao, Q.M., Shao, X.Q., Zhang, J.A., 2019.
na

Aberrant Histone Methylation in Patients with Graves’ Disease. Int. J. Endocrinol. 2019.

https://doi.org/10.1155/2019/1454617
ur

Yu, Liangyu, Wu, S., Deng, Y., Lei, J., Yu, Lixiu, Li, W., 2019. Insulin resistance induced by
Jo

olanzapine and other second-generation antipsychotics in Chinese patients with schizophrenia: a

comparative review and meta-analysis. Eur. J. Clin. Pharmacol. https://doi.org/10.1007/s00228-

019-02739-5

Yuan, H., Mischoulon, D., Fava, M., Otto, M.W., 2018. Circulating microRNAs as biomarkers for

depression: Many candidates, few finalists. J. Affect. Disord. 233, 68–78.

https://doi.org/10.1016/j.jad.2017.06.058

39
Zhao, H., Xu, J., Pang, L., Zhang, Y., Fan, H., Liu, L., Liu, T., Yu, F., Zhang, G., Lan, Y., Bai, J., Li,

X., Xiao, Y., 2015. Genome-wide DNA methylome reveals the dysfunction of intronic

microRNAs in major psychosis. BMC Med. Genomics 8, 62. https://doi.org/10.1186/s12920-

015-0139-4

Zhubi, A., Veldic, M., Puri, N. V., Kadriu, B., Caruncho, H., Loza, I., Sershen, H., Lajtha, A., Smith,

R.C., Guidotti, A., Davis, J.M., Costa, E., 2009. An upregulation of DNA-methyltransferase 1

and 3a expressed in telencephalic GABAergic neurons of schizophrenia patients is also detected

in peripheral blood lymphocytes. Schizophr. Res. 111, 115–122.

of
https://doi.org/10.1016/j.schres.2009.03.020

Zotti, M., Dos Santos, E.A., Cagliari, D., Christiaens, O., Taning, C.N.T., Smagghe, G., 2018. RNA

ro
interference technology in crop protection against arthropod pests, pathogens and nematodes.

-p
Pest Manag. Sci. 74, 1239–1250. https://doi.org/10.1002/ps.4813
re
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 Figure captions

DNA
Methylation

Genetic
Predisposition

of
Histon Epigenetic
Modifications Alterations

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Major
psychosis

Non-coding
-p Environmental
Factors
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RNAs
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Figure 1: An overview of epigenetic mechanisms that play a role in major psychosis

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 MAJOR

of
PSYCHOSIS

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-p
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Figure 2: A summary of epigenetically altered genes in SZ and BD. ↓: Decrease/Downregulation;

↑: Increase/Upregulation; ac: acetylation; K: lysine; me2: di-methylation; me3: tri- methylation;
ur
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Table

Table 1: DNA methylation alterations in SZ and BD

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 Gene Function Finding Reference
Tolosa et al.,
FOXP2 Transcription factor Hypermethylation in SZ patients’ brain
2010
Type II transmembrane Hypermethylation in SZ and female BD
KEL Mill et al., 2008
glycoprotein patients

COX-2 Prostaglandin biosynthesis Hypomethylation in BD patients’ brain Rao et al., 2012

Hypomethylation in SZ and BD patients’ Abdolmaleky et

HTR2A Serotonin receptor
salvia al., 2011
Potassium channels’ Lower methylation of the KCNQ3 exon 11 in Kaminsky et
KCQN3

of
protein BD al., 2015
Catabolism of Chen et al.,
MAOA No difference in paranoid SZ and control
neurotransmitters 2012

ro
Higher methylation level in lymphocytes Popendikyte et
DRD2 Adenylyl cyclase inhibitor
than striata al., 1999

MB-COMT
Dissimilation of
neurotransmitters
-p
Decreased gene promoter methylation in SZ
and BD patients’ salvia
Nohesara et al.,
2011
Extracellular matrix
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Gene promoter hypermethylation in SZ Veldic et al.,
RELN glycoprotein, brain
patients’ brain 2004
development
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Conversion of L-glutamate Gene promoter hypermethylation in SZ Veldic et al.,

GAD1
to GABA patients’ brain 2004
Differentially methylated in SZ patients’ Wockner et al.,
NOS1 Nitric oxide synthase
na

brain 2014
Differentially methylated in SZ patients’ Wockner et al.,
AKT1 Serine/Threonine Kinase
brain 2014
Cell cycle progression and Hypomethylated in BD and SZ patients’
ur

WDR18 Mill et al., 2008

signal transduction brain
Neurotransmitter Hypomethylated in BD and SZ patients’
GRIA2 Mill et al., 2008
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metabolism brain
Microtubule-dependent
Hypomethylated in BD and SZ patients’
MARLIN1 transport of the GABA-B Mill et al., 2008
brain
receptor
Potassium channel,
Hypomethylated in BD and SZ patients’
KCNJ6 regulation of insulin Mill et al., 2008
brain
secretion
Cellular differentiation, Differentially methylated in SZ patients’
WNT1 Mill et al., 2008
neuronal development brain
44
 Differentially methylated in SZ patients’
NR4A2 Transcription factor Mill et al., 2008
brain
Hypermethylated in BD whereas Sugawara et al.,
TBC1D22A GTPase-activating protein
hypometylated in SZ 2018
Hypomethylation in BD patients’ brain,
HCG9 HLA complex Pal et al., 2015
sperm and blood
Çöpoğlu et al.,
BDNF Neurotrophic factor No difference in SZ and control blood
2016
Hypomethylation two CpG sites at exon 9 in Starnawska et
FAM63B Dopaminergic expression
BD patients al., 2016
Hypomethylation in deficit SZ patients Gao et al.,
MMP9 Matrix metalloprotease
compared to non-deficit SZ patients (blood) 2018

of
Hypomethylation in SZ and BD patients’
IGF2 Brain development Pai et al., 2019
brain

ro
EGR-1 Synaptic plasticity No difference in SZ and control blood Hu et al., 2019

GRIN-2B
Synaptic plasticity, brain
development
Cell growth and
-p
Hypomethylation in SZ patients’ blood

Hypermethylation in SZ patients’ leukocytes

Fachim et al.,
2019
Garcia-Ruiz et
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DDR1
differentiation and brain al., 2020
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Table 2: Abnormal expressed ncRNAs in BD and SZ

miRNA Function Main Finding Reference

Inhibition of cell migration Upregulation in glia cells of BD patients Bavamian et

miR-149
and proliferation (brain) al., 2015
Lai et al.,
Upregulation in SZ blood and cerebellum of
miR-34a Neural migration 2016; Choi et
BD patients
al., 2017
Suppression of Upregulation in extracellular vesicle Banigan et al.,
miR-29c
extracellular matrix genes extracted from BD brain 2013
Stress adaptation, dendrite Upregulation in SZ patients’ post-mortem Perkins et al.,
miR-7
growth brains and living SZ patients’ blood 2007
Perkins et al.,

miR-212 Neuronal development
Immune response, neural
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Downregulation in BD and SZ patients
2007
Downregulation in SZ patients’ blood

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miR-30a Liu et al., 2017
migration
Wei et al.,
miR-130b Neuronal differentiation Upregulation in SZ patients’ blood
2015

miR-432
PI3K/AKT/mTOR
signalling pathway cell
-p
Upregulation in SZ patients Lai et al., 2016
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proliferation
Suppression of Altered expression SZ patients’ post- Perkins et al.,
miR-30b
extracellular matrix genes mortem brains 2007
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Gene expression, Kuswanto et

miR-137 Association between miR-137 SNPs and SZ
regulation neurogenesis al., 2015
Gomafu Barry et al.,
Gene expression regulation Dysregulation in SZ
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(lncRNA) 2014)
Barry et al.,
MIAT (lncRNA) Neuronal development Downregulation in SZ patients’ blood
2014
DLG-2 N-methyl-D-aspartate Downregulation in SZ patients’ post- Polesskaya et
ur

(lncRNA) (NMDA) receptors mortem brains al., 2003

CCAT2, TUG1
Response to DNA damage Sayad et al.,
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and PANDA Upregulation in BD patients

and represses apoptosis 2019
(lncRNAs)
HOXA-AS2,
SPRY4-IT1, Fallah et al.,
Gene expression regulation Upregulation in female SZ patients
MEG3 (lncRNAs) 2019
AC006129.1
Gene expression regulation Upregulated in SZ patients Ni et al., 2020
(lncRNA)

46