Search

Schizophrenia (SCZ) is a chronic psychotic disorder that contributes significantly to disability, affecting behavior, thought, and cognition. It has long been known that there is a heritable component to schizophrenia; studies in both the pre-genomic and post-genomic era, however, have failed to elucidate fully the genetic basis for this complex disease. Epigenetic processes - broadly, those which contribute to changes in gene expression without altering the genetic code itself - may help to understand better the mechanisms leading to development of SCZ. The objective of this review is to synthesize current knowledge of the epigenetic mechanisms involved in schizophrenia. Specifically, DNA methylation studies in both peripheral and post-mortem brain samples in SCZ are reviewed, as are epigenetic mechanisms including histone modification. The promising role of non-coding RNA including micro-RNA (miRNA) and its role as a potential diagnostic and therapeutic biomarker is outlined, as are epigenetic age acceleration and telomere shortening. Finally, we discuss limitations in current knowledge and propose future research directions.

The pathogenesis of schizophrenia is considered to be multi-factorial, with likely gene-environment interactions (GEI). Genetic and environmental risk factors are being identified with increasing frequency, yet their very number vastly increases the scope of possible GEI, making it difficult to identify them with certainty. Accumulating evidence suggests a dysregulated complement pathway among the pathogenic processes of schizophrenia. The complement pathway mediates innate and acquired immunity, and its activation drives the removal of damaged cells, autoantigens and environmentally-derived antigens. Abnormalities in complement functions occur in many infectious and auto-immune disorders that have been linked to schizophrenia. Many older reports indicate altered serum complement activity in schizophrenia, though the data are inconclusive. Compellingly, recent genome-wide association studies suggest repeat polymorphisms incorporating the complement 4A (C4A) and 4B (C4B) genes as risk factors for schizophrenia. The C4A/C4B genetic associations have re-ignited interest not only in inflammation-related models for schizophrenia pathogenesis, but also in neurodevelopmental theories, because rodent models indicate a role for complement proteins in synaptic pruning and neurodevelopment. Thus, the complement system could be used as one of the ‘staging posts’ for a variety of focused studies of schizophrenia pathogenesis. They include GEI studies of the C4A/C4B repeat polymorphisms in relation to inflammation-related or infectious processes, animal model studies and tests of hypotheses linked to auto-immune diseases that can co-segregate with schizophrenia. If they can be replicated, such studies would vastly improve our understanding of pathogenic processes in schizophrenia through GEI analyses and open new avenues for therapy.

Schizophrenia is a serious psychotic disorder, with disabling symptoms and markedly reduced life expectancy. The onset is usually in late adolescence or early adulthood, which in time overlaps with the maturation of the brain including the myelination process. Interestingly, there seems to be a link between myelin abnormalities and schizophrenia. The oligodendrocyte-derived myelin membranes in the CNS are highly enriched for lipids (cholesterol, phospholipids and glycosphingolipids), thereby pointing at lipid homeostasis as a relevant target for studying the genetics and pathophysiology of schizophrenia. The biosynthesis of fatty acids and cholesterol is regulated by the sterol regulatory element binding protein (SREBP) transcription factors SREBP1 and SREBP2, which are encoded by the SREBF1 and SREBF2 genes on chromosome 17p11.2 and 22q13.2, respectively. Here we review the evidence for the involvement of SREBF1 and SREBF2 as genetic risk factors in schizophrenia and discuss the role of myelination and SREBP-mediated lipid biosynthesis in the etiology, pathophysiology and drug treatment of schizophrenia.

Epigenetics is the study of nucleotide modifications that are heritable and act as regulatory mechanisms without changing the nucleotide sequence of the genome. Exogenous cues such as environment, lifestyle, nutrition, stress, and psychological factors affect epigenetic mechanisms. This mechanism is in concordance with the genetic information that plays an important role during prenatal and postnatal life of an individual. Recent epigenetic studies have revealed the potential of epigenetics in elucidating the mechanisms of different diseases. In this review, we discuss basic epigenetic mechanisms and their roles in health and disease. In addition, reported aberrations in epigenetic regulation for some common human diseases are described. Finally, we address some epigenetic approaches that have shown potential for targeted treatment of diseases.علم التخَلُّق هو دراسة التعديلات النوكليوتيدية المورَّثة التي تعمل كآلية تنظيمية دون تغيير التسلسل النيوكليوتيدي للجينوم. تؤثر إشارات خارجية مثل البيئة، ونمط الحياة، والتغذية، والإجهاد والعوامل النفسية على آليات التخَلُّق. وتتوافق هذه الآلية مع المعلومات الجينية التي تلعب دورا مهما في حياة الفرد قبل الولادة وبعدها. لقد كشفت الدراسات الأخيرة في علم التخَلُّق إمكانات علم التخَلُّق في توضيح آليات أمراض مختلفة لم يتم فهمها سابقا بشكل كامل.ناقشنا في هذا الاستعراض آليات التخَلُّق الأساسية ودورها في الصحة والمرض. إضافة إلى ذلك فقد تم وصف الانحرافات في التنظيم التخلُّقي التي تم تسجيلها لبعض الأمراض البشرية الشائعة. وأخيرا، تتناول الورقة بعض الأساليب في علم التخَلُّق، التي تكمن بها القدرة على العلاج الموجَّه للأمراض.

Epigenetics is the study of reversible modifications to chromatin and their extensive and profound effects on gene regulation. To date, the role of epigenetics in personalized medicine has been under-explored. Therefore, this review aims to highlight the vast potential that epigenetics holds.We first review the cell-specific nature of epigenetic states and how these can vary with developmental stage and in response to environmental factors. We then summarize epigenetic biomarkers of disease, with a focus on diagnostic tests, followed by a detailed description of current and pipeline drugs with epigenetic modes of action. Finally, we discuss epigenetic biomarkers of drug response.Epigenetic variation can yield information on cellular states and developmental histories in ways that genotype information cannot. Furthermore, in contrast to fixed genome sequence, epigenetic patterns are plastic, so correcting aberrant, disease-causing epigenetic marks holds considerable therapeutic promise. While just six epigenetic drugs are currently approved for use in the United States, a larger number is being developed. However, a drawback to current therapeutics is their non-specific effects. Development of locus-specific epigenetic modifiers, used in conjunction with epigenetic biomarkers of response, will enable truly precision interventions.

DNA methylation of gene promoter regions represses transcription and is a mechanism via which environmental risk factors could affect cells during development in individuals at risk for schizophrenia. We investigated DNA methylation in patient-derived cells that might shed light on early development in schizophrenia. Induced pluripotent stem cells may reflect a “ground state” upon which developmental and environmental influences would be minimal. Olfactory neurosphere-derived cells are an adult-derived neuro-ectodermal stem cell modified by developmental and environmental influences. Fibroblasts provide a non-neural control for life-long developmental and environmental influences. Genome-wide profiling of DNA methylation and gene expression was done in these three cell types from the same individuals. All cell types had distinct, statistically significant schizophrenia-associated differences in DNA methylation and linked gene expression, with Gene Ontology analysis showing that the differentially affected genes clustered in networks associated with cell growth, proliferation, and movement, functions known to be affected in schizophrenia patient-derived cells. Only five gene loci were differentially methylated in all three cell types. Understanding the role of epigenetics in cell function in the brain in schizophrenia is likely to be complicated by similar cell type differences in intrinsic and environmentally induced epigenetic regulation., Epigenetics: A genome-wide picture in patient-derived cells Schizophrenia-associated differences in the DNA methylation status of patient-derived cells suggest it could affect early brain development. Mechanisms that control gene expression without altering the genetic code, such as DNA methylation, could explain how environmental risk factors contribute to schizophrenia in genetically susceptible individuals. Alan Mackay-Sim and colleagues from Griffith University, Australia, carried out genome-wide comparisons of DNA methylation in induced pluripotent stem (iPS) cells, olfactory neurosphere-derived cells and fibroblasts from patients and controls. Differences in the DNA methylation pattern between patient and control iPS cells, which could reflect what happens in the embryo, suggest a disease-associated effect very early on in development. Only five genes were differentially methylated in all three patient-derived cell types compared to controls. None of these genes has previously been associated with schizophrenia and may represent new targets for future research.

Schizophrenia and other psychoses are categorical psychiatric diagnoses corresponding to frequent and heterogeneous disorders. Their physiopathology still remains largely unknown despite numerous recent advances. In particular, the last decade has identified different types of genetic variants, thanks to emergence of high-throughput methods. These methods allow both the identification of rare variants with a large effect such as punctual mutations or copy-number variants and the identification of frequent variants with a limited effect such as polymorphisms. Many impacted genes have been identified showing a very high genetic heterogeneity of psychoses. These genes are overrepresented in synaptic and neurotransmission pathways. Only a small fraction of psychoses could be easily explained by genetics but this screening in clinical practice is important as it can lead to therapeutic challenge or genetic counselling. Nowadays, it is clear that the pathophysiology of the psychoses can only be understood by an integrative approach taking into account the interaction between genes and environment. This interaction could be mediated by the epigenome defined as the modification of gene expression without changes in DNA sequence. Epigenome is stable but could be modified by environmental factors. Several epigenetic mechanisms have been studied in psychosis, in particular the DNA methylation, the modification of histones and the microRNA. All of these mechanisms are under regulation by genetic factors and variants in these epigenetic-involved genes and cofactors have been also associated with schizophrenia. Thus, pathophysiology of psychosis is complex and morestudiesare needed before definitive conclusions. Altogether, the recent advances in the genetics and epigenetics of psychosis are promising and could open the way to a recategorization of these disorders as well as the identification of new therapeutic targets.

Schizophrenia is a severe mental disorder with a large genetic component. Recent genome-wide association studies (GWAS) have identified many schizophrenia-associated common variants. For most of the reported associations, however, the underlying biological mechanisms are not clear. The critical first step for their elucidation is to identify the most likely disease genes as the source of the association signals. Here, we describe a general computational framework of post-GWAS analysis for complex disease gene prioritization. We identify 132 putative schizophrenia risk genes in 76 risk regions spanning 120 schizophrenia-associated common variants, 78 of which have not been recognized as schizophrenia disease genes by previous GWAS. Even more significantly, 29 of them are outside the risk regions, likely under regulation of transcriptional regulatory elements contained therein. These putative schizophrenia risk genes are transcriptionally active in both brain and the immune system, and highly enriched among cellular pathways, consistent with leading pathophysiological hypotheses about the pathogenesis of schizophrenia. With their involvement in distinct biological processes, these putative schizophrenia risk genes, with different association strengths, show distinctive temporal expression patterns, and play specific biological roles during brain development.

Epigenetics refers to potentially heritable processes that can mediate both lasting and transient changes in gene expression in the absence of genome sequence alterations. The field of epigenetics has introduced a novel understanding of the mechanisms through which the environment can shape an individual and potentially its offspring. This Mini-Review examines the current literature exploring the role of epigenetics in the development of mood disorders such as depression. Depression is twofold more common in females, yet the majority of preclinical research has been conducted exclusively in male subjects. Here we discuss what is known about sex differences in epigenetic regulation and function and how this may contribute to the etiology and onset of mood disorders. © 2016 Wiley Periodicals, Inc.

Suicide is a common occurrence in psychiatric disorders and is a cause of increased healthcare utilization worldwide. Schizophrenia is one of the most common psychiatric disorders worldwide and posited to be seen in 1% of the population worldwide. Suicide is a common occurrence in schizophrenia with 25%–30% patients with schizophrenia attempting suicide and 8%–10% completing it. There is a need for valid biological markers to help clinicians identify patients with schizophrenia that may be at a risk of suicide and thus help in them receiving better care and interventions at the earliest even before a suicide attempt occurring. There are clear neurobiological changes at a genetic, neuroimaging, and neurochemical level that occurs in patients with schizophrenia that attempt suicide. There is a new theory that postulates neuronal plasticity and neuroprotection to have a role in the biological changes that ensue when suicidal thoughts and feelings occur in patients with schizophrenia. Neurotrophic growth factors like brain-derived neurotrophic factor (BDNF) have been documented to play a role in the protection of neurons and in the prevention of neurobiological changes that may lead to suicide both in schizophrenia and depression. The present paper presents a commentary that looks at the role of BDNF as a protective factor and neurobiological marker for suicide in schizophrenia.

Schizophrenia is a severe disorder affecting approximately 1% of the population. Historically, alterations of dopaminergic function were considered the primary cause of schizophrenia. However, for many patients, drugs that alter dopaminergic function do not consistently lead to resolution of the symptoms of schizophrenia. Thus, there is an increased interest in pathophysiologic processes that result in altered neurodevelopment and plasticity associated with schizophrenia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in neurogenesis, synaptic plasticity, cognition, and neurotransmission. Genetic polymorphism, expression, and function of BDNF have been implicated in psychiatric diseases, including schizophrenia. This review discusses BDNF, its role in neurologic processes, and the evidence implicating BDNF in schizophrenia.

BACKGROUND Cognitive dysfunction has been recognized as a cardinal feature of schizophrenia. Elucidating the neurobiological substrates of cognitive dysfunction in schizophrenia would help identify the underlying mechanism of this disorder. The rs1064395 single nucleotide polymorphism, within the gene encoding neurocan (NCAN), is reported to be associated with schizophrenia in European populations and may influence brain structure in patients with schizophrenia. METHODS In this study, we aimed to explore whether NCAN rs1064395 confers some risk for schizophrenia and cognitive dysfunction in Han Chinese. We recruited 681 patients with schizophrenia and 699 healthy subjects. Two hundred and fifty-four patients were evaluated according to Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). RESULTS There were no significant differences in genotype or allele distributions of the rs1064395 polymorphism between the schizophrenia and control groups. Patients showed significantly poorer performance than controls on immediate memory, visuospatial skill, language, attention, delayed memory, and total RBANS score. Patients with the A/A or A/G genotype of rs1064395 had lower scores of immediate memory, visuospatial skill, attention, and total RBANS score than those with the G/G genotype. We performed an expression quantitative trait loci analysis and observed a significant association between rs1064395 and NCAN expression in the frontal (P=0.0022, P=0.022 after Bonferroni correction) and cerebellar cortex (P=0.0032, P=0.032 after Bonferroni correction). CONCLUSION Our findings indicate that this single nucleotide polymorphism may be a risk factor for cognitive dysfunction in patients with schizophrenia. Further investigations are warranted for validation purposes and to identify the precise mechanism by which rs1064395 influences cognitive performance in patients with schizophrenia.

Sensitization is defined as a process whereby repeated intermittent exposure to a given stimulus results in an enhanced response at subsequent exposures. Next to robust findings of an increased dopamine synthesis capacity in schizophrenia, empirical data and neuroimaging studies support the notion that the mesolimbic dopamine system of patients with schizophrenia is more reactive compared with healthy controls. These studies led to the conceptualization of schizophrenia as a state of endogenous sensitization, as stronger behavioral response and increased dopamine release after amphetamine administration or exposure to stress have been observed in patients with schizophrenia. These findings have also been integrated into the neurodevelopmental model of the disorder, which assumes that vulnerable neuronal circuits undergo progressive changes during puberty and young adulthood that lead to manifest psychosis. Rodent and human studies have made an attempt to identify the exact mechanisms of sensitization of the dopaminergic system and its association with psychosis. Doing so, several epigenetic and molecular alterations associated with dopamine release, neuroplasticity, and cellular energy metabolism have been discovered. Future research aims at targeting these key proteins associated with sensitization in schizophrenia to enhance the knowledge of the pathophysiology of the illness and pave the way for an improved treatment or even prevention of this severe psychiatric disorder.

Background: Epigenetic research in mental health has grown exponentially during the last decade and holds what some claim are “revolutionary” potentials for the development of new interdisciplinary models of mental ill health. Schizophrenia is the most appropriate diagnosis against which to assess progress in this regard.\ud Method: Papers on epigenetics and schizophrenia identified in a systematic literature search are subject to a conceptually-driven narrative review that assesses the relations between schizophrenia and epigenetics; considers some issues associated with empirical studies; and thereby identifies key assumptions guiding this research.\ud Findings: The revolutionary potentials of epigenetics are thus far not being realised due to various influences, including a preponderance of hypotheses that begin from a primarily biological question; the “condensation” of environmental influences and their effective reduction to their molecular consequences; and a frequent reliance upon animal studies that effectively preclude some important influences already established as relevant to this diagnosis.\ud Conclusion: Epigenetic research in schizophrenia (and mental health generally) could benefit from being more thoroughly interdisciplinary, from testing hypotheses that foreground social as well as biological influences, and from reconsidering its reliance upon psychiatric diagnoses.

Schizophrenia is a chronic, disabling neuropsychiatric disorder with complex genetic origins. The development of strategies for genome manipulation in rodents provides a platform for understanding the pathogenic role of genes and for testing novel therapeutic agents. Neuregulin 1 (NRG1), a critical developmental neurotrophin, is associated with schizophrenia. The NRG1 gene undergoes extensive alternative splicing and, to date, little is known about the neurobiology of a novel NRG1 isoform, NRG1-IV, which is increased in the brains of individuals with schizophrenia and associated with genetic risk variation. Here, we developed a transgenic mouse model (NRG1-IV/NSE-tTA) in which human NRG1-IV is selectively overexpressed in a neuronal specific manner. Using a combination of molecular, biochemical, electrophysiological, and behavioral analyses, we demonstrate that NRG1-IV/NSE-tTA mice exhibit abnormal behaviors relevant to schizophrenia, including impaired sensorimotor gating, discrimination memory, and social behaviors. These neurobehavioral phenotypes are accompanied by increases in cortical expression of the NRG1 receptor, ErbB4 and the downstream signaling target, PIK3-p110δ, along with disrupted dendritic development, synaptic pathology, and altered prefrontal cortical excitatory–inhibitory balance. Pharmacological inhibition of p110δ reversed sensorimotor gating and cognitive deficits. These data demonstrate a novel role for NRG1-IV in learning, memory, and neural circuit formation and a potential neurobiological mechanism for schizophrenia risk; show that deficits are pharmacologically reversible in adulthood; and further highlight p110δ as a target for antipsychotic drug development.SIGNIFICANCE STATEMENTSchizophrenia is a disabling psychiatric disorder with neurodevelopmental origins. Genes that increase risk for schizophrenia have been identified. Understanding how these genes affect brain development and function is necessary. This work is the first report of a newly generated humanized transgenic mouse model engineered to express human NRG1-IV, an isoform of the NRG1 (Neuregulin 1) gene that is increased in the brains of patients with schizophrenia in association with genetic risk. Using behavioral neuroscience, molecular biology, electrophysiology, and pharmacology, we identify a role for NRG1-IV in learning, memory, and cognition and determine that this relates to brain excitatory–inhibitory balance and changes in ErbB4/PI3K/AKT signaling. Moreover, the study further highlights the potential of targeting the PI3K pathway for the treatment of schizophrenia.

Schizophrenia is a severe mental illness that afflicts nearly 1% of the world population. Although the exact pathophysiology of schizophrenia is unknown, the N-methyl-d-aspartate receptor (NMDAR), a major glutamate receptor subtype, has received great attention. The NR1 subunit is often considered indispensable for functional NMDAR assemblies, abnormal modulation of which is found in patients with schizophrenia. In this review, we discuss how disrupted function of NR1 subunits in NMDAR leads to the progression and development of symptoms of schizophrenia-like behaviors in a variety of genetically modified mouse models. We also discuss some of the susceptible genes and shared signaling pathways among the schizophrenia, and how their mutations lead to NR1 subunits hypofunction. Finally, we suggest that the subunit-selective modulators of NR1 subunits in NMDA receptors may be promising tools for the therapy of schizophrenia.

Nearly 60 years ago Seymour Kety proposed that research on genetics and brain pathology, but not on neurochemistry, would ultimately lead to an understanding of the pathophysiology of schizophrenia. This article will demonstrate the prescience of Kety's proposal; advances in our knowledge of brain structure and genetics have shaped our current understanding of the pathophysiology of schizophrenia. Brain-imaging techniques have shown that schizophrenia is associated with cortical atrophy and ventricular enlargement, which progresses for at least a decade after the onset of psychotic symptoms. Cortical atrophy correlates with negative symptoms and cognitive impairment, but not with psychotic symptoms, in schizophrenia. Studies with the Golgi-staining technique that illuminates the entire neuron indicate that cortical atrophy is due to reduced synaptic connectivity on the pyramidal neurons and not due to actual loss of neurons. Results of recent genetic studies indicate that several risk genes for schizophrenia are within two degrees of separation from the N-methy-D-aspartate receptor (NMDAR), a subtype of glutamate receptor that is critical to synapse formation and synaptic plasticity. Inactivation of one of these risk genes that encodes serine racemase, which synthesizes D-serine, an NMDAR co-agonist, reproduces the synaptic pathology of schizophrenia. Thus, widespread loss of cortical synaptic connectivity appears to be the primary pathology in schizophrenia that is driven by multiple risk genes that adversely affect synaptogenesis and synapse maintenance, as hypothesized by Kety.

BACKGROUND Although genetic factors are risk factors for schizophrenia, some environmental factors are thought to be required for the manifestation of disease. Epigenetic mechanisms regulate gene functions without causing a change in the nucleotide sequence of DNA. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates synaptic transmission and plasticity. It has been suggested that BDNF may play a role in the pathophysiology of schizophrenia. It is established that methylation status of the BDNF gene is associated with fear learning, memory, and stressful social interactions. In this study, we aimed to investigate the DNA methylation status of BDNF gene in patients with schizophrenia. MATERIAL AND METHODS The study included 49 patients (33 male and 16 female) with schizophrenia and 65 unrelated healthy controls (46 male and 19 female). Determination of methylation pattern of CpG islands was based on the principle that bisulfite treatment of DNA results in conversion of unmethylated cytosine residues into uracil, whereas methylated cytosine residues remain unmodified. Methylation-specific PCR was performed with primers specific for either methylated or unmethylated DNA. RESULTS There was no significant difference in methylated or un-methylated status for BDNF promoters between schizophrenia patients and controls. The mean duration of illness was significantly lower in the hemi-methylated group compared to the non-methylated group for BDNF gene CpG island-1 in schizophrenia patients. CONCLUSIONS Although there were no differences in BDNF gene methylation status between schizophrenia patients and healthy controls, there was an association between duration of illness and DNA methylation.

Schizophrenia is a neuropsychiatric disorder of complex etiology. Human endogenous retroviruses (HERVs) have been presented as possible candidates explaining the connections between the genetic, infectious, neurodevelopmental, and neuroinflammatory aspects of schizophrenia, with the human endogenous retrovirus type W family (HERV-W) showing the greatest evidence of association. Studies have identified retroviral nucleotide sequences, envelope and capsid proteins, and elevated transcription of HERV-W elements in CSF, blood, and brain samples from individuals with schizophrenia. The HERV-W elements can trigger the immune system in a variety of ways. HERV genetic elements may be activated by various prenatal maternal infections, leading to neuroinflammation and genetic abnormalities, altering the development of the brain, and eventually culminating in the development of schizophrenia. This review presents a concise synthesis of available evidence and theoretical speculation regarding the role of HERV-W in schizophrenia. The need for further investigation is highlighted before any conclusions can be stated with confidence.

Epigenetic variability (DNA methylation/demethylation, histone modifications, microRNA regulation) is common in physiological and pathological conditions. Epigenetic alterations are present in different tissues along the aging process and in neurodegenerative disorders, such as Alzheimer's disease (AD). Epigenetics affect life span and longevity. AD-related genes exhibit epigenetic changes, indicating that epigenetics might exert a pathogenic role in dementia. Epigenetic modifications are reversible and can potentially be targeted by pharmacological intervention. Epigenetic drugs may be useful for the treatment of major problems of health (e.g., cancer, cardiovascular disorders, brain disorders). The efficacy and safety of these and other medications depend upon the efficiency of the pharmacogenetic process in which different clusters of genes (pathogenic, mechanistic, metabolic, transporter, pleiotropic) are involved. Most of these genes are also under the influence of the epigenetic machinery. The information available on the pharmacoepigenomics of most drugs is very limited; however, growing evidence indicates that epigenetic changes are determinant in the pathogenesis of many medical conditions and in drug response and drug resistance. Consequently, pharmacoepigenetic studies should be incorporated in drug development and personalized treatments.

DNA is not the only information passed from generation to generation. There are heritable modifications which do not involve changes in DNA sequence. The study of these modifications is called epigenetics. Many epigenetic mechanisms have been discovered including DNA methylation and histone alterations (methylation, acetylation, phosphorylation, ubiquitination). RNA molecules are also involved and important to proper processing or regulation of the DNA-encoded information. Diet, environment and lifestyle play the key roles in initiating epigenetic programming. Somatic health and especially male reproduction are shaped by epigenetics.

DNA methylation (DNAm) is important in brain development and is potentially important in schizophrenia. We characterized DNAm in prefrontal cortex from 335 non-psychiatric controls across the lifespan and 191 patients with schizophrenia and identified widespread changes in the transition from prenatal to postnatal life. These DNAm changes manifest in the transcriptome, correlate strongly with a shifting cellular landscape and overlap regions of genetic risk for schizophrenia. A quarter of published genome-wide association studies (GWAS)-suggestive loci (4,208 of 15,930, P < 10(-100)) manifest as significant methylation quantitative trait loci (meQTLs), including 59.6% of GWAS-positive schizophrenia loci. We identified 2,104 CpGs that differ between schizophrenia patients and controls that were enriched for genes related to development and neurodifferentiation. The schizophrenia-associated CpGs strongly correlate with changes related to the prenatal-postnatal transition and show slight enrichment for GWAS risk loci while not corresponding to CpGs differentiating adolescence from later adult life. These data implicate an epigenetic component to the developmental origins of this disorder.

The growing epidemic of obesity and diabetes, the aging population as well as prevalence of drug abuse has led to significant increases in the rates of the closely associated acute and chronic kidney diseases, including diabetic nephropathy. Furthermore, evidence shows that parental behavior and diet can affect the phenotype of subsequent generations via epigenetic transmission mechanisms. These data suggest a strong influence of the environment on disease susceptibility and that, apart from genetic susceptibility, epigenetic mechanisms need to be evaluated to gain critical new information about kidney diseases. Epigenetics is the study of processes that control gene expression and phenotype without alterations in the underlying DNA sequence. Epigenetic modifications, including cytosine DNA methylation and covalent post-translational modifications of histones in chromatin, are part of the epigenome, the interface between the stable genome and the variable environment. This dynamic epigenetic layer responds to external environmental cues to influence the expression of genes associated with disease states. The field of epigenetics has seen remarkable growth in the past few years with significant advances in basic biology, contributions to human disease, as well as epigenomics technologies. Further understanding of how the renal cell epigenome is altered by metabolic and other stimuli can yield novel new insights into the pathogenesis of kidney diseases. In this review, we have discussed the current knowledge on the role of epigenetic mechanisms (primarily DNAme and histone modifications) in acute and chronic kidney diseases, and their translational potential to identify much needed new therapies.

Epigenetics is a quickly growing field encompassing mechanisms regulating gene expression that do not involve changes in the genotype. Epigenetics is of increasing relevance to neuroscience, with epigenetic mechanisms being implicated in brain development and neuronal differentiation, as well as in more dynamic processes related to cognition. Epigenetic regulation covers multiple levels of gene expression; from direct modifications of the DNA and histone tails, regulating the level of transcription, to interactions with messenger RNAs, regulating the level of translation. Importantly, epigenetic dysregulation currently garners much attention as a pivotal player in aging and age-related neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, where it may mediate interactions between genetic and environmental risk factors, or directly interact with disease-specific pathological factors. We review current knowledge about the major epigenetic mechanisms, including DNA methylation and DNA demethylation, chromatin remodeling and non-coding RNAs, as well as the involvement of these mechanisms in normal aging and in the pathophysiology of the most common neurodegenerative diseases. Additionally, we examine the current state of epigenetics-based therapeutic strategies for these diseases, which either aim to restore the epigenetic homeostasis or skew it to a favorable direction to counter disease pathology. Finally, methodological challenges of epigenetic investigations and future perspectives are discussed.

Schizophrenia is a severe and highly complex neurodevelopmental disorder with an unknown etiopathology. Recently, immunopathogenesis has emerged as one of the most compelling etiological models of schizophrenia. Over the past few years considerable research has been devoted to the role of innate immune responses in schizophrenia. The findings of such studies have helped to conceptualize schizophrenia as a chronic low-grade inflammatory disorder. Although the contribution of adaptive immune responses has also been emphasized, however, the precise role of T cells in the underlying neurobiological pathways of schizophrenia is yet to be ascertained comprehensively. T cells have the ability to infiltrate brain and mediate neuro-immune cross-talk. Conversely, the central nervous system and the neurotransmitters are capable of regulating the immune system. Neurotransmitter like dopamine, implicated widely in schizophrenia risk and progression can modulate the proliferation, trafficking and functions of T cells. Within brain, T cells activate microglia, induce production of pro-inflammatory cytokines as well as reactive oxygen species and subsequently lead to neuroinflammation. Importantly, such processes contribute to neuronal injury/death and are gradually being implicated as mediators of neuroprogressive changes in schizophrenia. Antipsychotic drugs, commonly used to treat schizophrenia are also known to affect adaptive immune system; interfere with the differentiation and functions of T cells. This understanding suggests a pivotal role of T cells in the etiology, course and treatment of schizophrenia and forms the basis of this review.

Epigenetics refers to the acquisition and maintenance of heritable states of gene expression that occurs above the level of genetics through alterations in chromatin structure and accessibility. The field of epigenetics has moved much ahead from an emerging science and is growing at a faster pace, as there is increased realization about nutriment and nurture–epigenetic–phenotype relationship. Scientific studies concerning epigenetic changes in the genome in a systematic and genome-wide way provide clinching evidence for epigenetic interactions of environmental and lifestyle factors with genes and determine the reproductive outcomes and health. The epigenetic mechanisms are traditionally studied as DNA methylation, histone modifications, ATP-dependent chromatin remodeling, and noncoding RNA-mediated regulation. In the present review, we have presented an overview of the epigenetics evolved from the interaction and confluence of reproduction and nutrient environment. Besides, our experience with DNA methylation and chromatin modification of the cytochrome P450 aromatase (CYP19) gene is also presented. Understanding the emergence of paradigm shift in the reproductive epigenetics appears important as it will open up new vistas for viewing the impact of environment and dietary components on regulation of gene expression concerning the reproductive events and health conditions.

Epigenetics refers to functional alterations in gene expression or phenotype without any change of the underlying DNA sequence. It is the study of the potential of a cell or organism to express different traits through functional regulation of its gene transcription. Though it is met as a necessary process in biology, epigenetics may often play a crucial part in the development of specific pathologic conditions, including cardiovascular diseases and hypertension.

Schizophrenia, a debilitating disease with 1% prevalence in the general population, is characterized by major neuropsychiatric symptoms, including delusions, hallucinations, and deficits in emotional and social behavior. Previous studies have directed their investigations on the mechanism of schizophrenia towards neuronal dysfunction and have defined schizophrenia as a 'neuron-centric' disorder. However, along with the development of genetics and systematic biology approaches in recent years, the crucial role of glial cells in the brain has also been shown to contribute to the etiopathology of schizophrenia. Here, we summarize comprehensive data that support the involvement of glial cells (including oligodendrocytes, astrocytes, and microglial cells) in schizophrenia and list several acknowledged glia-related genes or molecules associated with schizophrenia. Instead of purely an abnormality of neurons in schizophrenia, an additional 'glial perspective' provides us a novel and promising insight into the causal mechanisms and treatment for this disease.

Introduction: Epigenetics is the study of heritable modifications in gene expression that do not change the DNA nucleotide sequence. Some of the most thoroughly studied epigenetic mechanisms at present are DNA methylation, post-transcriptional modifications of histones, and the effect of non-coding RNA molecules. Gene expression is regulated by means of these mechanisms and disruption of these molecular pathways may elicit development of diseases. Development: We describe the main epigenetic regulatory mechanisms and review the most recent literature about epigenetic mechanisms and how those mechanisms are involved in different epileptic syndromes. Conclusion: Identifying the epigenetic mechanisms involved in epilepsy is a promising line of research that will deliver more in-depth knowledge of epilepsy pathophysiology and treatments. Resumen: Introducción: La epigenética es el estudio de los cambios heredables en el ADN sin afectar a las secuencia de nucleótidos. Entre los mecanismos de regulación epigenética, los más estudiados y conocidos hasta la fecha son la metilación del ADN, la modificación de las histonas y los ARN no codificantes. Mediante estos mecanismos se regula la expresividad génica y la alteración de los mismos puede llevar al desarrollo de patologías. Desarrollo: Describimos los principales mecanismos de regulación epigenética y realizamos una revisión de la bibliografía reciente sobre los mecanismos de regulación epigenética y su implicación en distintos síndromes epilépticos. Conclusión: La identificación de los mecanismos epigenéticos implicados en la epilepsia constituye una prometedora vía de investigación para profundizar en el conocimiento de la fisiopatología y terapéutica de esta enfermedad. Keywords: Epigenetics, Neurodevelopment, Epileptogenesis, Epilepsy, Palabras clave: Epigenética, Neurodesarrollo, Epileptogénesis, Epilepsia

The apolipoprotein E (APOE) gene is robustly linked with numerous physiological conditions, including healthy aging, altered cardiovascular fitness, and cognitive function. These connections have been established primarily by phenotype-genotype association studies using APOE’s three common genetic variants (ε2, ε3, and ε4). These variants encode for the three apoE protein isoforms (E2, E3, and E4), which have slightly different structures and, consequently, distinct functions in lipid metabolism. However, the differential lipid binding and transferring properties of these isoforms cannot fully explain the association of APOE with such a wide range of physiological phenotypes. One potential explanation for APOE’s pleiotropic roles may lie in its unique epigenetic properties. In this article, we present a brief review of the APOE gene and protein, its disease associations, and epigenetic components, with a focus on DNA methylation. We close with a discussion of the prospective epigenetic implications of APOE in disease.

The concept of epigenetics is now providing the mechanisms by which cells transfer their new environmental-change-induced phenotypes to their daughter cells. However, how extracellular or cytoplasmic environmental cues are connected to the nuclear epigenome remains incompletely understood. Recently emerging evidence suggests that epigenetic changes are correlated with metabolic changes via chromatin remodeling. As many human complex diseases including cancer harbor both epigenetic changes and metabolic dysregulation, understanding the molecular processes linking them has huge implications for disease pathogenesis and therapeutic intervention. In this review, the impacts of metabolic changes on cancer epigenetics are discussed, along with the current knowledge on cancer metabolism and epigenetics.

Mitochondria play a critical role in regulating cellular functions including bioenergetics, calcium homeostasis, redox signalling, and apoptotic cell death. Mitochondria are also essential to many aspects of neurodevelopment and neuronal functions. However, mitochondrial impairment may affect bioenergetics in the developing brain and alter critical neuronal processes leading to neurodevelopmental abnormalities. Schizophrenia is a chronic and severe neuropsychiatric disorder of neurodevelopmental origin. Immuno-inflammatory pathway is one of the widely appreciated mechanisms that has consistently been implicated in the neurodevelopmental origin of schizophrenia. However, the source of inflammation and the underlying neurobiological mechanisms leading to schizophrenia are yet to be fully ascertained. Recent understanding reveals that perturbation of mitochondrial network dynamics might lead to various nervous system disorders with inflammatory pathologies. Mitochondrial deficit, altered redox balance and chronic low-grade inflammation are evident in schizophrenia. It is hypothesized that oxidative/nitrosative stress responses due to mitochondrial dysfunctions might activate immuno-inflammatory pathways and subsequently lead to neuroprogressive changes in schizophrenia. Herein, we summarise the current understanding of molecular links between mitochondrial dysfunctions and pathogenesis of schizophrenia based on evidence from genomics, proteomics and imaging studies, which together support a role for mitochondrial impairment in the pathogenetic pathways of schizophrenia.

Schizophrenia is a heterogeneous psychiatric disorder broadly accepted being caused by genetic and environmental factors. Although conventional genetic studies have identified some candidate genes for schizophrenia, low odds ratios and penetrance, and a lack of reproducibility have limited their explanatory power. Despite the major efforts made toward identifying environmental factors in schizophrenia, methodological limitations and inconsistent findings of epidemiological reports have obstructed attempts to identify exogenous causal factors. Epigenetic mechanisms, mediating between environment and genes, have recently been proposed to play an important role in the pathogenesis of schizophrenia. DNA methylation is the most stable and well-characterized epigenetic modification. In this paper, we briefly introduce DNA methylation mechanisms, genome-wide DNA methylation studies, and identify specific genomic methylation sites in individuals diagnosed with schizophrenia. The outline candidate genes such as Reelin and COMT, are also outlined before paying attention to the conundrum of recent researches.

Over the last decade, transcriptome studies of postmortem tissue from subjects with schizophrenia revealed that synaptic, mitochondrial, immune system, gamma-aminobutyric acidergic, and oligodendrocytic changes are all integral parts of the disease process. The combined genetic and transcriptomic studies argue that the molecular underpinnings of the disease are even more varied than the symptomatic diversity of schizophrenia. Ultimately, to decipher the pathophysiology of human disorders in general, we will need to understand the function of hundreds of genes and regulatory elements in our genome and the consequences of their overexpression and reduced expression in a developmental context. Furthermore, integration of knowledge from various data sources remains a monumental challenge that has to be systematically addressed in the upcoming decades. In the end, our success in interpreting the molecular changes in schizophrenia will depend on our ability to understand the biology using innovative ideas and cannot depend on the hope of developing novel, more powerful technologies.

Epigenetic aging is associated with several biological mechanisms and diseases. We assessed two brain data sets, one small (n = 48) and one large (n = 392), to test epigenetic aging in schizophrenia. DNA methylation age from frontal cortex was significantly correlated with chronological age but no significant differences in DNA methylation age acceleration between schizophrenia cases and controls were observed in both data sets. Our results were consistent with a previous study investigating schizophrenia and epigenetic aging in superior temporal gyrus. Future studies targeting different brain regions and defined cell types are warranted to further investigate accelerated brain aging in schizophrenia.

Schizophrenia is a chronic psychiatric disorder with a lifetime prevalence of about 1% in the general population. Recent studies have shown that Neuregulin-1 (Nrg1) is a candidate gene for schizophrenia. At least 15 alternative splicing of NRG1 isoforms all contain an extracellular epidermal growth factor (EGF)-like domain, which is sufficient for Nrg1 biological activity including the formation of myelin sheaths and the regulation of synaptic plasticity. It is known that Nrg1 can be cleaved by β-secretase (BACE1) and the resulting N-terminal fragment (Nrg1-ntf) binds to receptor tyrosine kinase ErbB4, which activates Nrg1/ErbB4 signaling. While changes in Nrg1 expression levels in schizophrenia still remain controversial, understanding the BACE1-cleaved Nrg1-ntf and Nrg1/ErbB4 signaling in schizophrenia neuropathogenesis is essential and important. In this review paper, we included three major parts: (1) Nrg1 structure and cleavage pattern by BACE1; (2) BACE1-dependent Nrg1 cleavage associated with schizophrenia in human studies; and (3) Animal studies of Nrg1 and BACE1 mutations with behavioral observations. Our review will provide a better understanding of Nrg1 in schizophrenia and a potential strategy for using BACE1 cleavage of Nrg1 as a unique biomarker for diagnosis, as well as a new therapeutic target, of schizophrenia.

Schizophrenia is a major psychiatric disorder that afflicts about 1% of the world's population, falling into the top 10 medical disorders causing disability. Existing therapeutic strategies have had limited success on cognitive impairment and long-term disability and are burdened by side effects. Although new antipsychotic medications have been launched in the past decades, there has been a general lack of significant innovation. This lack of significant progress in the pharmacotherapy of schizophrenia is a reflection of the complexity and heterogeneity of the disease. To date, many susceptibility genes have been identified to be associated with schizophrenia. DTNBP1 gene, which encodes dysbindin-1, has been linked to schizophrenia in multiple populations. Studies on genetic variations show that DTNBP1 modulate prefrontal brain functions and psychiatric phenotypes. Dysbindin-1 is enriched in the dorsolateral prefrontal cortex and hippocampus, while postmortem brain studies of individuals with schizophrenia show decreased levels of dysbindin-1 mRNA and protein in these brain regions. These studies proposed a strong connection between dysbindin-1 function and the pathogenesis of disease. Dysbindin-1 protein was localized at both pre- and post-synaptic sites, where it regulates neurotransmitter release and receptors signaling. Moreover, dysbindin-1 has also been found to be involved in neuronal development. Reduced expression levels of dysbindin-1 mRNA and protein appear to be common in dysfunctional brain areas of schizophrenic patients. The present review addresses our current knowledge of dysbindin-1 with emphasis on its potential role in the schizophrenia pathology. We propose that dysbindin-1 and its signaling pathways may constitute potential therapeutic targets in the therapy of schizophrenia.

Purpose of Review Epigenetics is defined as mitotically heritable changes in gene expression that do not directly alter the DNA sequence. By implication, such epigenetic changes are non-genetically determined, although they can be affected by inherited genetic variation. Extensive evidence indicates that autoimmune diseases including type 1 diabetes are determined by the interaction of genetic and non-genetic factors. Much is known of the genetic causes of these diseases, but the non-genetic effects are less clear-cut. Further, it remains unclear how they interact to cause the destructive autoimmune process. This review identifies the key issues in the genetic/non-genetic interaction, examining the most recent evidence of the role of non-genetic effects in the disease process, including the impact of epigenetic effects on key pathways. Recent Findings Recent research indicates that these pathways likely involve immune effector cells both of the innate and adaptive immune response. Specifically, there is evidence of cell type-specific enrichment in altered DNA methylation, changes which were temporally stable and enriched at gene regulatory elements. Summary Epigenomics remains in its infancy, and we anticipate further studies will define how the interaction of genetic and non-genetic effects induces tissue-specific destruction and enhances our ability to predict, and possibly even modify that process.

The diatheses of gene and environment interaction in schizophrenia (SCZ) are becoming increasingly evident. Genetic and epigenetic backgrounds are being considered in stratifying and addressing phenotypic variation and drug response in SCZ. But how much of these epigenetic alterations are the primary contributing factor, toward disease pathogenesis and drug response, needs further clarity. Evidence indicates that antipsychotic drugs can also alter the epigenetic homeostasis thereby inducing pharmacoepigenomic effects. We re-examine the context of epigenetics in disease pathogenesis and antipsychotic drug therapy in SCZ to understand how much of these observations act as real indicators of the disease or therapeutic response. We propose that epigenetic viewpoint in SCZ needs to be critically examined under the genetic, epigenetic and pharmacoepigenetic background.

Several lines of evidence suggest schizophrenia is a segmental progeria, that is, some but not all aspects of accelerated aging may be present. However, the evidence has not been consistent. Problems with matching and confounding may account for some of these discrepancies. Given the etiopathophysiological heterogeneity of schizophrenia, it is possible that only a specific pathophysiological group within schizophrenia is associated with progeroid features, while others are not, or that one group is associated with a particular segment of aging features, while other progeroid features are found in another pathophysiological subgroup. In the aging research field, significant progress has been made in identifying the molecular pathways that confer aging: epigenetic changes, inflammation, proteostasis, adult stem cell function, metabolic changes, and adaptation to stress, and macromolecular damage. In addition to replication and clarification of existing kinds of evidence, examining these aging pathways would improve our understanding of progeria in schizophrenia.

Background: Approximately one-third of patients with schizophrenia are considered treatment resistant. For these patients, the atypical antipsychotic drug clozapine is recommended as the only evidence-based treatment available. However, there is still significant variability in treatment response and many patients suffer side effects. Animal studies have demonstrated that clozapine influences histone modification and DNA methylation, and a recent EWAS study in humans identified multiple differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in clozapine-exposed samples. In the current study, we used a longitudinal, within-participant design to conduct genome-wide analysis of DNA methylation changes in treatment-resistant patients over 6 months of clozapine use.

Schizophrenia occurs in ∼25% of individuals with 22q11.2 deletion syndrome (22q11.2DS), the strongest known molecular genetic risk factor for schizophrenia. This review highlights recent literature in 22q11.2DS as it pertains to psychosis and schizophrenia.Advances in noninvasive prenatal testing allow for early detection of 22q11.2DS in utero, whereas premature birth has been shown to be a significant risk factor for development of psychotic illness in 22q11.2DS. Impairments in various domains of cognitive and social functioning, as well as neuroanatomical alterations, are comparable with those in other high-risk groups and may serve as early signs of psychosis in 22q11.2DS. Novel research on the pathogenesis of schizophrenia in 22q11.2DS using cellular and mouse models indicates changes in expression of genes within the 22q11.2 deletion region and elsewhere in the genome, implicating molecular pathways involved in schizophrenia and associated neurocognitive deficits. Increased risks of obesity and of Parkinson's disease in 22q11.2DS warrant consideration in antipsychotic management.Progress in characterizing and predicting psychotic illness in 22q11.2DS supports this identifiable subpopulation as a molecular model with important implications for understanding the pathogenesis of schizophrenia in the general population and for development of potential novel therapies.

Epigenetics is involved in the altered expression of gene networks that underlie insulin resistance and insufficiency. Major genes controlling β-cell differentiation and function, such as PAX4, PDX1, and GLP1 receptor, are epigenetically controlled. Epigenetics can cause insulin resistance through immunomediated pro-inflammatory actions related to several factors, such as NF-kB, osteopontin, and Toll-like receptors. Hereafter, we provide a critical and comprehensive summary on this topic with a particular emphasis on translational and clinical aspects. We discuss the effect of epigenetics on β-cell regeneration for cell replacement therapy, the emerging bioinformatics approaches for analyzing the epigenetic contribution to type 2 diabetes mellitus (T2DM), the epigenetic core of the transgenerational inheritance hypothesis in T2DM, and the epigenetic clinical trials on T2DM. Therefore, prevention or reversion of the epigenetic changes occurring during T2DM development may reduce the individual and societal burden of the disease.

Metabotropic glutamate receptor subtype 5 (mGluR5), encoded by the GRM5 gene, represents a compelling novel drug target for the treatment of schizophrenia. mGluR5 is a postsynaptic G-protein coupled glutamate receptor strongly linked with several critical cellular processes that are reported to be disrupted in schizophrenia. Accordingly, mGluR5 positive allosteric modulators show encouraging therapeutic potential in preclinical schizophrenia models, particularly for the treatment of cognitive dysfunctions against which currently available therapeutics are largely ineffective. More work is required to support the progression of mGluR5-targeting drugs into the clinic for schizophrenia treatment, although some obstacles may be overcome by comprehensively understanding how mGluR5 itself is involved in the neurobiology of the disorder. Several processes that are necessary for the regulation of mGluR5 activity have been identified, but not examined, in the context of schizophrenia. These processes include protein-protein interactions, dimerisation, subcellular trafficking, the impact of genetic variability or mutations on protein function, as well as epigenetic, post-transcriptional and post-translational processes. It is essential to understand these aspects of mGluR5 to determine whether they are affected in schizophrenia pathology, and to assess the consequences of mGluR5 dysfunction for the future use of mGluR5-based drugs. Here, we summarise the known processes that regulate mGluR5 and those that have already been studied in schizophrenia, and discuss the consequences of this dysregulation for current mGluR5 pharmacological strategies. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.

Schizophrenia is a pervasive neuropsychiatric disorder affecting over 1% of the world’s population. Dopamine system dysfunction is strongly implicated in the etiology of schizophrenia. Data support the long-standing concept of schizophrenia as a disease characterized by hyperactivity within midbrain (striatal D2) dopamine systems. In addition, there is now considerable evidence that glutamate neurotransmission, mediated through NMDA-type receptors, is deficient in patients with schizophrenia and that hypoactivity in cortical dopamine and glutamate pathways is a key feature of this serious mental disorder. While current antipsychotic medications—with a common mechanism involving dopamine D2 receptor antagonism or pre-synaptic partial agonism—adequately address positive symptoms of the disease, such as the acute hallucinations and delusions, they fail to substantially improve negative features, such as social isolation, and can further compromise poor cognitive function associated with schizophrenia. In fact, cognitive impairment is a core feature of schizophrenia. The treatment of cognitive impairment and other residual symptoms associated with schizophrenia, therefore, remains a significant unmet medical need. With current cell-surface receptor-based pharmacology falling short of addressing these core cognitive symptoms, more recent approaches to treatment development have focused on processes within the cell. In this review, we discuss the importance of cyclic nucleotide (cNT) phosphodiestereases (PDEs)—intracellular enzymes that control the activity of key second messenger signaling pathways in the brain—which have been proposed as targets for new schizophrenia therapies. We also discuss the challenge facing those developing drugs to target specific PDE enzymes involved in psychopathology without involving other systems that produce concomitant side effects.

Epigenetics is a quickly expanding field encompassing mechanisms regulating gene expression without involving changes in the DNA sequence. It is of increasing relevance to neurobiologic symptoms including brain aging and psychiatric disorders. In this chapter, we attempt to review the current understanding about three major mechanisms of epigenetic regulation—DNA methylation, histone modifications, and posttranscriptional regulation by noncoding RNAs, such as microRNAs and long noncoding RNAs, and summarize the major findings of the significant impact that epigenetics has on brain aging as well as psychiatric disorders. In addition, promising epigenetics-based interventions and therapeutic strategies targeting brain aging and psychiatric diseases are briefly discussed.

The epigenetic machinery comprised of processes, such as DNA methylation, histone modifications, and noncoding RNA, contribute to heritable changes in gene expression or phenotype. These epigenetic changes do not involve changes in the actual DNA sequence and consist of an ever-expanding array of other epigenetic processes mediated by prions, Polycomb proteins, and higher-order chromatin organization, as well as many others. Innovative technology has driven the field of epigenetics, and the development of novel model organisms of epigenetics has also contributed to remarkable progress in epigenetics. Moreover, epigenetic processes are important in many functions that impact a vast number of organisms. Epigenetics has also influenced evolution and epigenetic epidemiology has demonstrated the intricate role between epigenetics and the environment. Finally, a number of human diseases, such as cancer, brain disorders, and metabolic syndromes have been associated with aberrations in epigenetic processes that now open a new area of advances in epigenetic therapy.