Neuropsychiatric Disorders and Epigenetics

Neuropsychiatric Disorders and Epigenetics, Second Edition is a comprehensive reference on the epigenetic basis of common neuropsychiatric disorders. The volume is organized into chapters covering individual neuropsychiatric disorders, from addiction to anxiety and autism spectrum disorders, and is contributed by leading experts in their respective fields. The epigenetic aspects of each disorder are discussed, in the context of the full range of associated epigenetic mechanisms, including DNA modification, histone post-translational modification, chromatin organization, and non-coding RNA. A particular emphasis is placed on potential epigenetic interventions, when the effects of environmental stimuli on epigenetic states is particularly relevant to disease.

This new edition has been fully updated to reflect recent research advances enabled by genomic technologies, as well as therapeutic interventions for previously unmanageable disorders. Several new chapters have been added on disorders or approaches not considered in the earlier edition, including epigenetics and anxiety disorders, epigenetics and neuroimaging in neuropsychiatric disorders, genome-wide approaches to epigenetic research, and the epigenetics of spinal muscular atrophy. By helping to define epigenetics as a key player in neuropsychiatric disorders, this volume empowers new research, clinical translation, and pharmacological advances, and highlights promising directions for ongoing investigation.

• Analyzes the effects of environmental stimuli on epigenetic states that correlate with neuropsychiatric disease induction
• Reviews the epigenetic basis for common neuropsychiatric disorders, thereby guiding translational therapies for clinicians and mechanistic studies for scientists
• Features extensive use of diagrams, illustrations, tables, and graphical abstracts for each section to reinforce understanding
• Includes chapter contributions from leading global experts

• Language: English
• Publisher: Academic Press
• Release date: Sep 29, 2023
• ISBN: 9780443185175

Book preview

Preface

We are pleased to release the second edition of Neuropsychiatric Disorders and Epigenetics. Like the first edition, this edition considers neuropsychiatric disorders in a broad sense, that is, disorders that involve the brain in their pathogenesis and have a psychiatric component in their clinical manifestation. Most of the chapters included in the first edition have been updated in the second edition to present the latest available information in the respective areas. A new chapter, Epigenetics and Anxiety Disorders, has been added in this edition.

This edition, like its predecessor, belongs to the Translational Epigenetics series being published by Elsevier under the leadership of Dr. Trygve O. Tollefsbol, Professor of Biology, University of Alabama, Birmingham, USA. Dag H. Yasui, who coedited the first edition of this book with us, was unfortunately unavailable to coedit this edition. We thank all the chapter authors for their very good contributions. We thank Peter Linsley of Elsevier for initiating the work on this edition and Mathew Mapes, also of Elsevier, for helping us put all the chapters together.

J. Peedicayil

Vellore, India

D. R. Grayson

Chicago, IL, United States

Section 1

Neuropsychiatric disorders and epigenetics: general aspects

Outline

Chapter 1. Introduction to Neuropsychiatric disorders and epigenetics

Chapter 2. Environmental factors and epigenetics of neuropsychiatric disorders

Chapter 3. Epigenetic biomarkers in neuropsychiatric disorders

Chapter 1: Introduction to Neuropsychiatric disorders and epigenetics

Jacob Peedicayil ¹ , and Dennis R. Grayson ²       ¹ Department of Pharmacology and Clinical Pharmacology, Christian Medical College, Vellore, Tamil Nadu, India      ² Department of Psychiatry, College of Medicine, University of Illinois, Chicago, IL, United States

Abstract

This chapter discusses the concepts of psychiatry, neurology, and neuropsychiatry. These are interrelated disciplines that involve the study of disorders which have the commonality that they all affect the brain. The history of neuropsychiatry is outlined. The chapter also highlights the potential importance of epigenetics in the pathogenesis and management (prevention, diagnosis, and treatment) of neuropsychiatric disorders. Epigenetics may help fulfill the long-felt need of biomarkers and new drugs for the management of neuropsychiatric disorders. Most neuropsychiatric disorders are heritable, implicating a genetic component in their etiology. However, the genetics of these disorders is complex, and, in general, environmental factors significantly contribute to this complexity and the interactions underlying the role that genes play in the pathophysiology of these disorders. One long-term goal of current research in the field is to use epigenetic mechanisms to potentially identify peripheral biomarkers that are both diagnostic and that are informative for the use of drugs used for the management of these disorders.

Keywords

Epigenetics; Neurology; Neuropsychiatric; Neuropsychiatry; Psychiatry

1. Introduction

Epigenetics, which literally means above or in addition to genetics, involves molecular mechanisms that include DNA methylation and demethylation, histone modifications, and noncoding RNA-mediated regulation of gene expression. Collectively, DNA and histone modifications along with chromatin remodeling proteins play a critical role in regulating chromatin structure [1]. In turn, alterations in chromatin architecture lead to changes in gene expression by allowing transcription factor access to key gene regulatory regions (e.g., promoters and enhancers). In general, epigenetic mechanisms lead to changes in the levels of open and closed chromatin across the genome, hence simultaneously impacting the expression profile of numerous genes.

Epigenetics is attracting ever-increasing interest in virtually every branch of medicine [2–4] and indeed, has been referred to as the epicenter of modern medicine because it can help to explain the relationships between an individual's genetic background, the environment, aging, and disease prognosis [5]. Epigenetics is also predicted to provide information for the prevention and treatment of disease by providing novel biomarkers, drug targets, and associated drugs [5,6]. It has also been suggested that epigenetics will help usher in an era of personalized medicine, which is characterized by the ability to treat patients on an individualized basis [7,8]. Like in other branches of medicine, the importance of epigenetics in the pathogenesis and management of psychiatric disorders is becoming increasingly appreciated, and epigenetics is an active area of research in psychiatry since the first decade of this century [9]. This book discusses the role of epigenetics in the pathogenesis and management of neuropsychiatric disorders.

2. Neuropsychiatry and neuropsychiatric disorders

Neuropsychiatry bridges conventional boundaries interposed between the mind and the brain [10,11]. It is an integrative and collaborative field that avoids specialty-derived, reductionist categorizations that recognize and address only circumscribed features of a specific brain-based illness [10,11]. A major focus of neuropsychiatry is the assessment and treatment of the cognitive, behavioral, and affective (mood) symptoms of patients with disorders of the brain. Neuropsychiatry also encompasses the gray area between the subdisciplines of neurology and psychiatry (Fig. 1.1) [12]. Thus, there are very few neurological disorders without a psychiatric component and very few psychiatric disorders without a neurological component. Neuropsychiatry also includes psychiatric disorders that arise due to structural or pathological conditions outside the brain [13]. For example, several endocrine and metabolic disorders can result in psychiatric illness [14]. This can occur because the brain is very active metabolically, and hence neurons of the brain are very sensitive to alterations of cellular and metabolic processes of the body [13]. Neuropsychiatric disorders are sometimes referred to as neurobehavioral disorders [15,16].

Figure 1.1  Schematic showing the interrelationships between neurology, psychiatry, and neuropsychiatry.AD, Alzheimer's disease; HD, Huntington's disease; MDD, major depressive disorder; PTSD, posttraumatic stress disorder.

3. Historical outline of neuropsychiatric disorders

The Greek physician Hippocrates (c. 460–375 BCE) believed that the brain is the basis of the mind and that all psychopathology arises in the brain [17–19]. There were also opposing theories like the suggestion of Aristotle (384–322 BCE) that the brain's main function was to cool the blood [17]. Moreover, throughout the middle ages aspects of our mental lives were often linked to organs other than the brain, such as the heart [17]. At the advent of modern medicine during the 17th century, neurological and psychiatric disorders were not regarded as separate disciplines, but as a single discipline, namely, nervous diseases [20]. The concept of nervous diseases was consolidated and strengthened during the 18th century. It was during the 19th century that nervous diseases started to diverge into distinct disciplines. Disorders with a structural abnormality in the brain tended to be called neurological disorders. Disorders of the psychic apparatus of the brain tended to be called psychiatric disorders. Psychiatry was thought to be neurology without clinical signs [17]. This separation of psychiatry from neurology extended into the 20th century. For much of the 20th century, neurology and psychiatry were separated by an artificial boundary created by the divergence of philosophical approaches and by the research and therapeutic approaches toward them [21]. The major reasons for such a separation of these two disciplines was that on the one hand the triumphs of neuropathology and the clinicopathologic method led to neurology as a structurally based discipline; and on the other hand, to the growth of psychodynamic psychiatry with a conceptual framework of a psychic (functional) apparatus either separated from, or obscurely linked to, the brain [10]. The advent of psychoanalysis in the United States during the 1930s sharpened and intensified the separation between psychiatry and neurology. Psychiatry and neurology became two separate disciplines. Neurological disorders were thought to be due to pathological lesions in the brain. Psychiatric disorders were thought to be due to abnormal functioning of the brain due to genetic and psychosocial factors. Psychiatric patients were most often isolated in mental hospitals (or asylums) and psychiatry was divorced from the rest of medicine.

Modern research highlights the difficulties caused by a predominantly organic, structurally-based neurology and a predominantly psychic functionally-based psychiatry because in neurology there is growing evidence that structurally based disorders have a functional component. Thus, several neurological disorders like epilepsy, brain tumors, and cerebrovascular accidents are accompanied by behavioral, psychological, and cognitive deficits [22–24]. In psychiatry the discovery of structural lesions based on modern imaging techniques such as computerized tomography and magnetic resonance imaging are proving difficult to integrate with functional disorders [18]. For instance, psychiatric disorders like schizophrenia [25] and bipolar disorder [26] are now known to be accompanied by structural lesions in the brain. Indeed, some workers regard schizophrenia [27] and bipolar disorder [28] as neuropsychiatric disorders. The neurological disorder N-methyl-D-aspartate (NMDA) encephalitis can be clinically indistinguishable from acute schizophrenia, a psychiatric disorder [29,30]. The etiological role of psychosocial factors in disorders of the brain was thought to demarcate psychiatric disorders from neurological disorders, with psychosocial factors acting only in psychiatric disorders. However, now it is thought that psychosocial factors act via epigenetic mechanisms in the pathogenesis of psychiatric disorders, that is, through biological mechanisms [31–33]. Hence, there is a lot that unites psychiatry and neurology, and little that divides them, much like two sides of the same coin. At the same time, there are differences between neurology and psychiatry. For instance, psychotherapy is of major importance in the treatment of certain psychiatric disorders and only of minimal importance in the treatment of neurological disorders. Hence, instead of merging psychiatry and neurology into one discipline, they can be considered to be two subdisciplines of neuropsychiatry [34,35], which in turn can be considered to come under neurosciences [21,36]. The interest in, and scope of, neuropsychiatry is expanding, attracting a lot of attention in recent years [37].

4. Neuropsychiatric disorders and epigenetics

As is well known, the brain is the most complex and complicated organ in the human body [38]. The human brain comprises about 100 billion neurons interconnected in wide variety of neural circuits [39]. The human genome, which contains 20,000–24,000 genes [40], is unlikely to have the encoded information to specify this level of complexity. Hence, another layer of information, namely epigenetic regulation of gene expression, is used to coordinate patterns of gene expression during development and in the adaptive functioning of the human brain. Environmental factors are thought to impact gene expression by altering epigenetic mechanisms of gene expression, and ncRNAs appear to be a major substrate for environment–epigenome interactions [41].

Epigenetics is known to play a major role in the development and functioning of the human brain. This is not surprising because epigenetic mechanisms are known to have played a major role in the evolution of the human brain [42]. When an individual's brain develops, the three main types of cells in the brain, neurons and glial cells (astrocytes and oligodendrocytes), are formed from neural stem cells, which are cells that possess the ability to self-renew and differentiate into the three main cell types in the brain [43]. Epigenetic mechanisms play an important role in regulating gene expression in this process by orchestrating alterations in chromatin architecture [43]. These mechanisms also play a major role in the whole-scale transformation over time of the mid-gestational human brain into the adult human brain. Indeed, since so many genes are differently transcribed, the fetal and adult human brains can almost be considered to be two different organs [44]. Even after birth, the human brain is an ever-changing organ encoding memories and directing behavior, and epigenetics is thought to play a major role in the changes involved [45]. Epigenetics is known to play a role in various functions and states of the brain like synaptic transmission [46], memory and neuronal plasticity [47,48], cognition and behavior [49], neuroendocrinology [50], neuroimmunology [51], and neuroinflammation [52]. Since epigenetic mechanisms of gene expression play a major role in the normal development and functioning of the brain, it is not surprising that abnormalities in epigenetic mechanisms of gene expression contribute to disorders of the brain. Indeed, there is growing evidence that epigenetic mechanisms underlie a wide range of neuropsychiatric disorders [53].

This book discusses the role of epigenetics in a wide range of important neuropsychiatric disorders. Some of the disorders like autism spectrum disorders, intellectual disability, attention-deficit hyperactivity disorder, and Down's syndrome typically first manifest in infants and children. Others like the cognitive disorders, Alzheimer's disease, Parkinson's disease, and cerebrovascular accidents typically first manifest in elderly individuals. Yet others like multiple sclerosis, migraine, drug addiction, and eating disorders typically first manifest between these age groups. An earlier book, Epigenetics in Psychiatry [54] discussed the role of epigenetics in disorders like schizophrenia, bipolar disorder, and major depressive disorder, which are not covered in detail in this book. The earlier book also covered disorders like cognitive disorders, autism spectrum disorders, intellectual disability, and drug addiction. Since the current book belongs to a Translational Epigenetics series, translational aspects of the epigenetics of such disorders are emphasized in this book.

5. Epigenetics and neuropsychiatric disorders: Translational aspects

The ultimate objective of medical research is to improve the clinical management of patients, in terms of diagnosis, prevention, and treatment. Each of these requires translational research, that is, using discoveries made in the laboratory to improve patient care. In this context, research on the epigenetics of neuropsychiatric disorders may well prove to be valuable and useful. It has been suggested [55,56] that research on the epigenetics of neuropsychiatric disorders could prove to be useful in the diagnosis of these disorders by providing reliable and disorder-specific biomarkers. In addition, this research could aid in the prevention of these disorders since abnormal epigenetically regulated patterns of gene expression are potentially reversible. Similarly, research, which is directed at the identification of novel drug targets in the treatment of these disorders, may lead to the identification of novel drugs. Research has already shown that dietary modification, psychotherapy, electroconvulsive therapy, and physical exercise all correct abnormal epigenetic mechanisms of gene expression. Each of these interventional modalities may be useful in the clinical management of patients with neuropsychiatric disorders.

Abbreviations

ncRNAs    Noncoding RNAs

NMDA    N-methyl-D-aspartate

Glossary

Functional    Without a physiological or anatomical cause

Neurological disorders    Disorders affecting the brain, spinal cord, or the nerves

Neuropsychiatric disorders    Disorders of mood, cognition, and behavior that arise from overt disorder in cerebral function, or indirect effects of extracerebral disease

Psychiatric disorders    Psychiatric or mental disorders are disorders that affect an individual's thinking, feeling, mood, and behavior

Psychic    Of or relating to the mind

Psychoanalysis    A systematic structure of theories concerning the relationship between conscious and unconscious psychological processes propounded by Sigmund Freud. A technical procedure for investigating unconscious mental processes and for treating neurotic disorders

Psychodynamic psychiatry    An approach to the diagnosis and treatment of psychiatric patients based on the principles of psychoanalysis

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Chapter 2: Environmental factors and epigenetics of neuropsychiatric disorders

Jacob Peedicayil     Department of Pharmacology and Clinical Pharmacology, Christian Medical College, Vellore, Tamil Nadu, India

Abstract

Brain development is highly plastic due to rapid changes in cell numbers and neural connectivity that together allow the integration of a broad scope of intrinsic and environmental cues important for normal function and the risk for disease. While cellular mechanisms have been well known for their role in neuronal plasticity, the role of epigenetic mechanisms, notably DNA methylation and posttranslational histone modifications, has emerged more recently. Epigenetic marks serve to inscribe environmental experiences at the level of DNA and chromatin, thus generating long-lasting, though potentially reversible, memory traces of the past. In this chapter, the developmental, physiological, and molecular framework by which psychological, social, and other environmental factors are thought to impact the epigenome of neuronal cells with a role in the pathogenesis of neuropsychiatric disorders is reviewed.

Keywords

Early-life adversity; Early-life stress; Epigenetic programming; Epigenetics; HPA axis

1. Introduction

The advent of molecular genetics during the last century and the identification of causative mutations involved in rare monogenic diseases have contributed to the popular belief that genetic variation may explain most, or even all, of our physical and mental conditions including our susceptibility to various diseases [1]. At the same time, the complexity of the human genome has been simplistically reduced to an immutable master plan drafted with the inception of our lives that will inescapably determine our biologic destiny [1]. However, an unexpected result from the completion of the Human Genome Project was the finding that the number of genes in the human genome is similar to that of Caenorhabditis elegans and that more than 95% of the human genome exhibits no protein-coding information [2,3]. These discoveries revived current interest in molecular epigenetic mechanisms to explain how the complex variation of human cells and tissues can be explained by the orchestrated expression of a limited number of genes [4]. In this context, the epigenome is thought of as the collection of epigenetic marks that instructs each cell to correctly interpret the invariable DNA-based genetic blueprint. Importantly, epigenetic marks respond to the environment and can lead to long-term, but reversible, adjustments in gene-regulatory networks underlying the function of different physiological systems in tissues and even whole organs. Among these, the human brain plays an important role and is tasked to mediate between an ever-changing environment and the preset genetic blueprint. Indeed, the emerging field of neuropsychiatric epigenetics suggests that our heritage undergoes steady transitions whereby genes influence our lives but also where our lives influence the actions of our genes [5].

In this chapter the role of neuronal plasticity in the light of new findings from epigenetics is discussed and the way by which molecular mechanisms of early-life experiences are engraved into the epigenome is briefly discussed. Later, how psychological, social, nutritional, and other factors can affect physiological systems during sensitive windows of neurodevelopment to program long-term regulatory adjustments that can increase the risk for future psychiatric disease are explored. It is proposed that early-life adversity (ELA) and malnutrition, among additional factors, share in common an activation of the stress system and that epigenetic mechanisms may sustain such activated states far beyond the initial trigger.

2. The epigenetic dimension of neuroplasticity

For a long time neuroscientists have been intrigued by the nature versus nurture debate when considering individual differences in life course trajectories and the effects of early-life events on the prevalence, severity, and course of neuropsychiatric disorders [6]. While the genetic blueprint continuously instructs early development, the organism remains highly receptive to environmental cues. Hence, different phenotypes can arise from a single genotype by the processes of developmental plasticity [7]. As a case in point, the female honeybee can develop into either a worker or a queen depending on how the early larva is fed. Such developmental plasticity enables an organism to cope with ever-changing environments by modulation of its phenotypic development and life course. While commonly viewed as an adaptive reaction, environmentally-induced adjustments are also thought to increase the risk for later disease when these changes do not match future needs (what is referred to as the mismatch hypothesis) [7]. On the other hand, environmentally induced adjustments in regulatory set points and thresholds can also disrupt homeostatic control mechanisms under normative conditions and hence confer an increased risk for disease (what is referred to as the risk hypothesis). While these hypotheses remain subject to ongoing debate, neuroplasticity is most prevalent when rapid changes in cell numbers, structure, and connectivity co-occur (pre- and postnatally, but also during puberty) and declines with increasing age [8].

The human brain develops through a highly organized process that starts before birth and continues into adulthood [9]. At the end of the embryonic period rudimentary structures of the central nervous system are laid down, which evolve continuously through the end of gestation. This embryonic stage comprises the formation and fast growth of cortical and subcortical structures including the establishment of fiber pathways. Gross morphological changes of the prenatal neural system predetermine its later architectural organization and concur with the generation of neurons from human embryonic day 41 onward until major parts of neurogenesis are completed by mid-gestation. Rudimentary neural networks arise once neurons have migrated to their final destination and undergo further elaboration in response to various internal and environmental cues. Importantly, brain development subsists postnatally for an extended period of time, and structural changes frequently underlie changes in functional reorganization of processes controlling emotion, behavior, and cognition among other higher functions. Throughout the developing brain, levels of connectivity surpass by far those seen in adults and are gradually pruned back through competitive processes that interconnect to experiences of an organism. These regulatory processes are essential for cellular plasticity and provide the capacity for adaptation, for better or for worse, with possible lifelong consequences. The human brain preserves a lifelong capacity for structural neuroplasticity (i.e., turnover of synaptic connections, expansion and contraction of dendritic trees, and a limited amount of neurogenesis), although there are periods in life where the brain is more sensitive to the effects of experience. Such sensitive periods concern the formation of specific circuits that underlie specific abilities like vision, hearing, language acquisition, and higher cognitive functions.

A growing body of literature suggests that epigenetically mediated modulation of the expression of specific genes and pathways also plays an important role in developmental plasticity [10]. While all cells of a multicellular organism are genetically identical, they are structurally and functionally distinct due to the differential expression of their genes. Molecular epigenetic mechanisms controlling gene expression orchestrate various developmental processes including cell differentiation, X-chromosome inactivation in females, and genomic imprinting [11]. By extension, the same epigenetic mechanisms are thought to operate in neuroplasticity [5]. Since developmental plasticity involves dynamic changes in gene expression, epigenetic mechanisms coordinating gene regulation may be transient or persist across the life course. The honeybee referred to earlier exemplifies how epigenetic processes contribute to developmental plasticity. Although the duration of access to royal jelly determines whether larvae develop into queens or workers, experimental silencing of the gene-encoding DNA methyltransferase 3, an enzyme which adds new methylation marks to CpG dinucleotides (see Section 2.3.1), causes most larvae to become queens [12]. In support of this finding, growing evidence indicates that epigenetic mechanisms can leave a lasting footprint at regulatory gene regions in response to the environment and thus contribute to the programming of risk phenotypes [13,14].

Taken together, neurodevelopment comprises critical windows of sensitivity during which environmental experiences can impact on neuronal substrates with lifelong consequences for the manifestation of distinct phenotypes. Although neuroplasticity has been traditionally ascribed to cellular and structural changes in response to environmental cues, molecular epigenetic mechanisms are increasingly recognized to modify the DNA and chromatin of neuronal cells in a stimulus-dependent manner and to trigger enduring changes in the expression of genes important for psychiatric phenotypes. In the next section, the principal aspects of molecular epigenetic mechanisms will be considered before tackling the question of what kind of physiological systems can mediate the effects of early-life experiences by epigenetic marking.

3. Molecular epigenetic mechanisms

The term epigenetics comes with different historical flavors that need to be clarified before we can discuss newer insights into the underlying molecular mechanisms. In 1940, the British biologist Conrad Waddington originally coined this neologism to conceptualize how genes might interact with the environment during development to give rise to different cellular and organismal phenotypes from the same genotype [15]. While Waddington did not postulate any mechanisms that could mediate these effects, Arthur Riggs thought of epigenetics as heritable changes in gene expression regulating cell fate decisions and final phenotypes independently of changes in DNA sequence [16]. Since then, major advancements in the understanding of DNA methylation, posttranslational modifications of histones, chromatin structure, nucleosome positioning, and more recently noncoding RNAs (ncRNAs), among others, have substantially advanced our perception of molecular epigenetics. Above all, DNA methylation and posttranslational histone modifications represent core concepts of molecular epigenetics that have been well studied over the last decades due to their role in the initiation and maintenance of long-lasting epigenetic states. In the context of this chapter, a snapshot of these two mechanisms will be provided to prepare for the subsequent sections and refer readers interested in a more comprehensive survey to a recent book [4].

3.1. Epigenetic tagging of DNA

DNA methylation describes the addition of a methyl group to the fifth carbon of the nucleotide base cytosine (5mC) that takes place in somatic cells primarily in the context of palindromic CpG dinucleotides. The existence of DNA methylation was hypothesized as early as 1925 although its functional role in gene expression was only recognized by studies on X-chromosome inactivation and cancer [17,18]. In addition to canonical DNA methylation, non-CpG methylation (CpH; H = A, T, or C) with a major role in plants has also been detected in embryonic stem cells, the developing nervous system of mice and humans, and even in adults. However, further studies are needed to define the poorly understood function of non-CpG methylation and its relevance to gene regulation [19].

A family of highly conserved DNA methyltransferases (DNMTs) consisting of Dnmt1, Dnmt3A, and Dnmt3B catalyze DNA methylation at symmetric CpG residues in mammals [19]. Dnmt1, jointly with its obligate partner Uhrf1 (ubiquitin-like plant homeodomain and RING finger domain), recognizes preferentially hemimethylated DNA as a substrate during DNA replication and thus preserves the parental strand's methylation pattern. In contrast, de novo methylation of DNA is mainly catalyzed by the transfer of methyl groups through Dnmt3A and Dnmt3B in conjunction with Dnmt3l. The latter encodes an enzymatically inactive homologue that due to its scaffolding function stimulates the catalytic activities of either Dnmt3 (Fig. 2.1). Except for punctuated stretches of DNA with a high CpG content, so-called CpG islands (CGIs), CpG sites are mostly depleted in the mammalian genome. CGIs localize to approximately 70% of all annotated promoters and commonly remain methylation-free. On the contrary, CpGs outside of CGIs typically undergo DNA methylation [19]. While in general, CGIs are most often methylation-free, CGIs overlaying promoter regions frequently acquire DNA methylation and gene silencing during cancer development. Prompted by these findings, DNA methylation has been commonly defined as an all-purpose repressive mechanism in gene regulation.

Figure 2.1  The Life Cycle of DNA Methylation in Mammalian Cells.Methylation of the nucleotide cytosine (C) occurs primarily in the context of CpG dinucleotides and is carried out either by the maintenance of DNA methyltransferase (DNMT1) during replication or by the de novo DNA methyltransferases (DNMT3A or DNMT3B). Demethylation of 5-methylcytosine (5mC) occurs through iterative oxidation by ten-eleven translocation proteins (TET1/2) and generates first 5-hydroxymethylcytosine (5hmC), then 5-formylcytosine (5fc), and finally 5-carboxycytosine (5caC). The latter, oxidation product is then efficiently excised by the DNA repair machinery (base excision repair, BER; nucleotide excision repair, NER). Alternatively, 5hmC can be directly deaminated to thymine, which is then recognized by G/T mismatch-specific thymine DNA glycosylase (TDG). Finally, the mismatched bases are replaced by the DNA repair machinery.

This one-sided definition needs, however, to be revised in the light of recent findings from genome-wide DNA methylation studies showing that the effects of DNA methylation actually depend on genomic location, sequence composition, and transcriptional status and can contribute to either gene activation or repression [19,20]. In addition, the classical concept that DNA methylation is an irreversible, covalent bond laid down during development needs to be reconsidered in view of the transformative discovery of active demethylation by the family of ten-eleven translocation (Tet) proteins [21]. This group of enzymes catalyzes iterative (or repetitive) cycles of oxidation that convert 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and ultimately 5-carboxycytosine (5aC) (Fig. 2.1). Interestingly, each of these modification states exists with a half-life indicating they may serve as yet not well-understood biological functions. The oxidized derivatives are poorly recognized by maintenance DNMT complexes and once bound, their catalytic activities are largely reduced. Consequently, Tet-mediated oxidation leads to replication-dependent dilution of the methylation mark on the parental strand during preimplantation and primordial development. Finally, excision of oxidized cytosines takes place by the DNA excision-repair machinery [base excision repair (BER); nucleotide excision repair (NER)] as has been suggested for embryonic stem cells [21]. As an alternative route to active demethylation, 5hmC can also be directly deaminated to thymine which is further processed by DNA glycosylases like TDG (G/T mismatch-specific thymine DNA glycosylase) (Fig. 2.1). Notably, clusters of 5hmC seem to be enriched at regulatory sites throughout the genome suggestive of an instructive role in gene regulation. A plausible explanation for this distinct pattern is provided by the finding that oxidized cytosines can impair the binding of proteins that recognize 5mC residues and thus turn off their regulatory functions [20]. Taken together, the DNA methylome is more dynamic than originally thought and can undergo iterative cycles of methylation and demethylation at regulatory sites important for gene expression.

3.2. Epigenetic tagging of histones

Core histones represent highly basic proteins that tightly package DNA to fit the limited nuclear space. This compressed state, termed chromatin, also provides a platform on which gene regulation is carried out, and modification of core histones represents an elaborate mechanism for epigenetic tagging of the genome. Histone modifications can take place in response to DNA methylation or by intracellular signaling pathways independent of DNA methylation [22].

In the nucleus, 146 base pairs of DNA are wound around a histone octamer comprising two copies of each core histone (i.e., H2A, H2B, H3, and H4) to generate a nucleosome, the building block of chromatin. Once nucleosomes are arrayed further into higher order structures in the presence of linker histones (i.e., H1) and other nonhistone proteins, they become mostly inaccessible to the transcriptional machinery. However, higher-order histone–DNA structures can be remodeled by different enzymatic and chromatin remodeling complexes, in order to regain access to regulatory regions targeted by the transcriptional machinery [22]. Structural studies indicate that the N-terminal tails of histones protrude beyond the nucleosome surface and can form a signal integration platform, where posttranslational modifications provide a signature that ultimately coordinates the activity of numerous transcription factors, associated cofactors, and the transcription machinery in general [22]. Specific amino acid residues on the free amino-terminal tails and on the globular core domains can serve as substrates for different kinds of posttranslational modifications comprising lysine acetylation, lysine and arginine methylation, serine phosphorylation, and covalent binding of ubiquitin, among others [22]. Taken together, epigenetic tagging of chromatin plays an important role in DNA packaging, gene transcription, cross-talk between DNA methylation and chromatin configuration, and ultimately, integration of intrinsic and environmental signals into the