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Name: Epigenetic Aspects of Chronic Diseases
Author: Helmtrud Roach, Felix Bronner,‎ Richard Oreffo
Book type: Manual
Published: 2011 y.
Size: 7.41 mb
Format: PDF
Publishing house: Springer Science+Business Media London.
Number of pages: 255

This book is dedicated to Trudy Roach, who initiated and developed this treatise. Shortly after formulating the outline, Trudy was diagnosed with bowel cancer. For over a year Trudy responded to treatment and continued her research, teaching, and editorial activities. In her last few months, even though treatment was no longer effective, Trudy remained optimistic, a source of inspiration, and gained pleasure from her varied scholarly activities and time with her family. In the name of Trudy, we also dedicate this book to the many victims of the diseases discussed here, with the hope that in the not too distant future effective treatment, based in part on epigenetic insights, will improve the quality of life of patients with these diseases.

A. Barry Kay
Felix Bronner
Richard Oreffo

Epigenetics refers to processes that alter gene expression without changes in DNA sequence. In development, for example, genes are turned on and off, causing changes in the phenotype, from fetus to adult. Epigenetic mechanisms also mediate environmentally induced changes that may result in disease states, as when people on a lowsugar diet are exposed to high sugar intakes in a new environment and develop diabetes. Indeed, as will be discussed in detail in this book, many chronic diseases are the result of epigenetically induced structural changes in the DNA, resulting in DNA hypo- and hypermethylation, which cause genes not normally expressed to be expressed, whereas other genes are no longer expressed.
Rebecca Smith and Jonathan Mill, in Chap. 1, provide an overview of the relationship between epigenetics and chronic disease. The chapter describes and discusses epigenetics and the epigenome, DNA methylation and changes in histone structure, and interactions between the two processes. Attention is called to the increasing evidence that external influences interact directly with the epigenome, leading to changes in epigenetic processes and gene expression of the individual. Human pathologies, e.g., cancer or imprinting disorders, involve epigenetic changes. Also, discordances between monozygotic twins have been ascribed to nongenetic factors, with epigenetics linking the environment to changes in the phenotype. Prenatal and early-life environmental factors appear to play a role in the etiology of chronic disease. An example cited by the authors is the finding that serious hunger during the Dutch winter of 1944 led to a higher incidence of disease in the children of pregnant women when they became adults. The chapter proceeds to discuss epigenetic mechanisms and how these may affect chronic disease treatment, and raises the question of transgenerational epigenetic inheritance, an issue of intense current research.
In Chap. 2, Ester Lara, Vincenzo Calvanese, Agustin F. Fernandez, and Mario Fraga describe in detail techniques to study DNA methylation and histone modification, both at the global and gene-specific level. DNA methylation can be studied by a variety of methods. This may involve a locus-specific study of the methylation status of a specific gene, or a genome-wide study, involving many genes, or analysis of the methylation status of a cell or tissue, i.e., a global study. One of the oldest techniques to study methylation is reverse-phase high-performance liquid chromatography. Other methods described in the chapter are immunochemical methods, the methyl group acceptance assay, the chloroacetaldehyde assay, the bisulfate assay, among others. The authors then describe several locus-specific assays, including the use of melting analysis. In addition to the many specific methylation methods, the authors proceed to histone analysis, both global and locus-specific. Throughout the chapter, the various methods are comprehensively described, analyzed, evaluated, tabulated, and reference-supported.
Chapter 3, by Marie-Pierre Lambert and Zdenko Herceg, discusses the mechanisms of epigenetic silencing. Recognizing that dysregulation of epigenetic mechanisms contributes to human disease, the authors describe the structure of chromatin, essential for the maintenance of geometric stability, and point out that permanent silencing of the transposable elements and non-coding sequences of DNA is mainly due to epigenetic mechanisms, notably DNA methylation, which regulates chromatin. The chapter details the steps and mechanisms involved in DNA methylation and indicates that regulation of gene expression requires a dynamic equilibrium between promoter regions, chromatin structure, and access for transcriptional regulatory factors. This involves histones, the principal proteins of chromatin, with the N-terminal region, the histone "tail" constituting the major site for epigenetic regulation. The authors then examine the role of microRNAs in the regulation of epigenetic silencing and the equilibrium between active and repressive marks in the chromatin structure, an equilibrium modulated by the interplay of epigenetic mechanisms. Epigenetic plasticity and genomic imprinting are discussed, as is X chromosome inactivation. The chapter concludes by calling attention to the fundamental role of gene silencing, with unscheduled silencing responsible for disease.
In vertebrates, cytosine methylation constitutes an epigenetic DNA modification involved in genome stability, gene repression, and gene imprinting, with incorrect DNA methylation patterns associated with various pathological situations. In Chap. 4, Thierry Grange and Edio E. Lourenço analyze the mechanisms of gene activation, with emphasis on the dynamics of DNA methylation and demethylation. The chapter describes what the authors call the methylation landscape, i.e., large-scale and genome-scale methylation maps, the regulation of promoter activity by DNA methylation, transcription-dependent gene-body methylation, and the link to chromatin. The authors then analyze epigenetic reprogramming of DNA demethylation, both global and local, and the mechanisms of DNA demethylation, pointing out that active demethylation mechanisms are akin to DNA repair mechanisms and may involve recruitment of DNA repair machinery. The controversial proposal that in vertebrates demethylation by a base excision repair pathway is initiated by a DNA glycosylase is discussed at length, with comparisons made to the process in plants. Demethylation by the nucleotide excision repair pathways is then taken up and analyzed, as are links to other pathways, with the chapter concluding that demethylation may function in the recruitment of methylation-sensitive transcription factors, rather than in regulating chromatin switches.
Paul Cloos, in Chap. 5, describes in molecular detail the essential role of histone demethylases, enzymes that catalyze the removal of methylation from histones. It is dysregulation or inappropriate positioning of these enzymes that appears to contribute or cause disease, particularly cancer. The chapter discusses the role of transcription factors pRB and p53 as tumor repressors and in inducing senescence, another repressor of carcinogenesis. Several other suppressor proteins are discussed in detail. For example, the question is asked whether JHDMIB histone demethylase is a tumor suppressor or an oncoprotein. Possible roles of demethylases in a variety of cancers are discussed - prostate, breast, hematopoietic, brain, and renal cancers - as well as the relationship of these enzymes to neural disorders (mental retardation, schizophrenia, autism, epilepsy, and neuropathy). Other conditions or disorders that may involve the demethylases are male infertility, obesity, congenital heart disease, and alopecia. The author concludes by anticipating that future research will uncover more insights into the pathogenetic role of these important enzymes.
Epigenetic mechanisms play a central regulatory role in the immune system, as discussed by Travis Hughes and Amr H. Sawalha in Chap. 6. The widely varying characteristics of T cell populations are largely the result of epigenetic modifications at key regulatory loci. The chapter discusses the regulatory, T helper as well as follicular T cells, and then proceeds to an evaluation of epigenetic dysregulation in systemic lupus erythematosus. The effect of promoter demethylation on gene overexpression in lupus is discussed, as is demethylation of the inactive X chromosome in lupus, the effect of DNA methylation inhibitors, signaling in the ERK pathway, histone modification, and chromatin remodeling. The chapter concludes with an analysis of the role of methyl-binding domain proteins, a brief discussion of the role of microRNAs, and reference to rheumatoid arthritis. As in other chapters, helpful figures and a thorough list of references complete the text.
Rheumatoid arthritis and the role of epigenetics are discussed in Chap. 7 by Alec M. Grabiec, Paul P. Tak, and Kris A. Reedquist. The disease is the outcome of a combination of genetic susceptibility factors, autoantibody production due to aberrant regulation of the immune system, and environmental factors, such as smoking or inappropriate nutrition. Change in the activation of a number of intracellular signaling pathways resulting from aberrant epigenetic modifications has, as discussed by the authors, led to better understanding of the pathobiology of the disease and to intensive search for new therapeutic targets. The chapter discusses global and promoter-specific modulation of DNA methylation, aberrant microRNA expression, the perturbation of histone acetyl transferase and histone deacetylase activity in rheumatoid arthritis, and includes findings on the targeting of that activity in animal models of the disease. The chapter concludes by emphasizing the relevance of epigenetic mechanisms for the pathogenic alterations in gene expression that lead to chronic inflammation and its persistence in rheumatoid arthritis, even though the mechanisms involved are not yet fully understood.
Osteoarthritis, a chronic disease that affects some two-thirds of the elderly population, is, as discussed by Helmtrud I. Roach in Chap. 8, a prominent example of how changes in the epigenetic status, specifically DNA methylation, affect disease evolution and progress. The chapter analyzes degradation and matrix changes of the articular cartilage, cellular and molecular changes, and evaluates the role of genetics in osteoarthritis. Evidence from monozygotic twin studies suggests a role for epigenetic changes induced by environmental factors. The chapter then discusses hypo- and demethylation at specific CpG sites in the DNA, in vitro studies that mimic changes in gene expression that occur in osteoarthritis, the role of 1L1-b expression, and describes secondary arthritis that results if developmental dysplasia of the hip in the young is not corrected. The energy hormone leptin is aberrantly expressed in osteoarthritis, varying inversely with DNA methylation status. Factors that affect DNA methylation are described and analyzed, with the chapter concluding that methylation of genomic DNA is a significant mechanism for regulating tissue-specific gene expression, but that the molecular steps that lead to changes in the methylation status remain unknown.
Type 2 diabetes mellitus, the incidence of which is rapidly increasing worldwide because of urbanization, physical inactivity, and increasing obesity in both adults and youngsters, is the outcome of a complicated interaction between genome and epigenome. Charlotte Ling, Tina Rőnn, and Marloes D. Nitert, in Chap. 9, describe the role of epigenetics in the evolution of type 2 diabetes, how undernutrition and low birth weight enhance the disease risk in later life, and how chromatin structure and DNA methylation affect beta cell lines. The chapter discusses oxidative phosphorylation in relation to the disease, the decline in beta cell proliferation, and the change in DNA methylation with increasing age. The authors then devote much attention to the importance and role of nutrition and obesity, both in human and animal model studies. The interaction between fat metabolism and type 2 diabetes is described, as is the role of leptin. Low physical activity is a risk factor for the disease, and the authors discuss the still limited number of studies that deal with the role of epigenetics in exercise. The chapter concludes with a discussion of diabetic complications and their relationship to epigenetic changes and emphasizes the importance epigenetic mechanisms play in the pathogenesis of type 2 diabetes.
Andrew L. Durham and Ian M. Adcock, in Chap. 10, discuss epigenetic regulation of asthma and allergic diseases. The chapter begins with a discussion of the four classes of hypersensitive responses: IgE mediated, IgG or IgM mediated, immune complex mediated, and cell-mediated hypersensitivity. The authors then turn their attention to asthma, to how allergy develops, and the importance of maternal imprinting, and analyze epigenetic mechanisms, imprinting, and epigenetic regulation of the immune response, with histone acetylation playing an important role. They discuss how environmental factors alter the epigenetic profile and how diet affects epigenetics and allergy. The chapter then details how exposure to environmental tobacco smoke is associated with impaired respiratory function and increases the risk of asthma. A similar correlation applies to air pollution. Exposure to particulate pollutants and to diesel exhaust has been shown to increase proinflammatory cytokines in utero, in animal models, and in human airway epithelial cells. Asthma is treated with glucocorticoids which modulate the epigenetic environment; the molecular mechanisms of the response are described in detail. Molecules that modulate histone acetyltransferase and histone deacetylase have been developed and used to restore glucocorticoid responsiveness. The authors conclude that epigenetics has immense potential to understand and treat preventable environmental disease.
Attempts at identifying genetic mechanisms for major mental diseases have not been successful. Indeed, analyses of the brain transcriptome by microarray assays have shown that hundreds of genes are differentially expressed in the affected brain regions of patients with these diseases, but not in most of their other tissues. Having made these points in their introduction to Chap. 11, Hamid Mostafavi-Abdomaleky, Stephen J. Glatt, and Ming T. Tsuang call attention to the fact that most psychiatric disorders are episodic and may have long-lasting periods of remission. Therefore genetic mutations alone cannot be responsible for the disease phenotypes, inasmuch as spontaneous remission and fluctuation do not occur in purely genetic diseases. Dysregulation of epigenetic machinery due to environmental factors can cause periods of remission. The authors then describe aberrant DNA methylation in psychiatric disease, as in Rett's syndrome, schizophrenia, in association with suicide and childhood abuse, in post-traumatic stress disorder, and as a result of smoking and in alcoholism. Aberrant histone modification also occurs in major mental diseases and is described next. A third molecular mechanism is dysregulation of microRNA, associated with schizophrenia and schizo-affective disorder. A number of highly expressed microRNAs in the superior temporal gyrus and the dorsolateral prefrontal cortex are known to be involved in the pathogenesis of schizophrenia. After discussing these mechanisms, the authors deal with epigenetic aberrations in relation to paternal effects, gender differences, and brain laterality. The chapter concludes by highlighting the importance and interrelationship of signal pathways and the need to study the epigenetic effects therein, in the hope that discoveries will lead to novel strategies to deal with these devastating diseases.
The relationship between epigenetics and mental disease is further developed in Chap. 12, where Axel Schumacher, Syed Bihaqi, and Nasser H. Zawia discuss lateonset Alzheimer's disease. The authors show that the molecular transition from memory encoding and initial consolidation to progressive long-term storage, retrieval, and reconsolidation involves complex layers of local and system-wide epigenetic modifications. In Alzheimer's disease gene expression in the brain is altered, with multiple functional and molecular pathways affected. Late-onset Alzheimer's disease is characterized by many non-Mendelian anomalies that suggest an epigenetic component. After listing and discussing these, the authors describe methylation homeostasis in this condition, for example, that some genes that play a central role in amyloid processing display significant epigenetic variability. Other components of the methylation pathway are also abnormal. Attention is called to the low folate level in the spinal fluid of Alzheimer patients and its effects. In the next section the authors discuss the effect of epigenetic drift, probably caused by high epigenetic turnover, and then summarize the evidence for an epigenetic fingerprint in Alzheimer's disease. The effects of DNA methylation and oxidation on the disease are reviewed in detail, with the conclusion raising the question whether epigenetic changes precede late-onset Alzheimer's disease, conferring disease risk, or whether epigenetic drift is the result. The authors favor the possibility that predisposition to the disease is related to DNA methylation profiles and influenced by epigenetic drift.
Epigenetic effects are particularly significant in development and the life course. The importance of epigenetic modification of fetal development and the resulting change in susceptibility in later life to noncommunicable diseases, such as metabolic syndrome, cardiovascular disease, osteoporosis, obesity, is discussed in detail in Chap. 13 by Keith M. Godfrey, Karen A. Lillycrop, Mark A. Hanson and Graham C. Burdge. The authors point out that links between prenatal growth and later disease risk reflect variations in the quality of the intrauterine environment, with prenatal nutrition as a major factor. The concept of predictive adaptive response is defined; it constitutes an integrated regulator in early life to meet the predicted later nvironment. The resulting phenotype implies a relatively constant postnatal environment. Otherwise the individual is "mismatched", resulting in a phenotype no longer appropriate for the actual environment the individual inhabits. The authors discuss the mismatch and then proceed to an evaluation of epigenetics during development and aging. Genomic imprinting is discussed, with most of the 53 human genes known to be imprinted located in CpG-rich domains where methylation of the CpG dinucleotides represses the maternal or paternal allele. Changes in the epigenetic regulation of genes due to nutrition and the effects of altered, nutrition-induced transcription are, it is pointed out, related to later diseases, both in humans and animal models. Interventions to prevent or reverse induced phenotypes are evaluated, transgenerational effects are discussed, and the chapter concludes with an analysis of the relevance of epigenetic processes to the risk of adult disease.
Active inflammatory genes are suppressed by histone deacetylases. Corticosteroids recruit deacetylases to switch off inflammatory genes. Histone deacetylases may therefore be a target for developing anti-inflammatory treatments, especially needed in diseases with active corticosteroid resistance, as in chronic obstructive pulmonary disease. This is the topic developed by Peter J. Barnes, in Chap. 14. After describing the disease with its progressive airflow limitation, due to remodeling and narrowing of small airways and the destruction of the lung parenchyma, the author analyzes the inflammation typical of the disease and then proceeds to a description of histone acetylation and deacetylation, the role of the histone deacetylase enzymes, the reduced activity of which in the alveolar macrophages of cigarette smokers is correlated with increased inflammatory gene expression. How glucocorticoids suppress inflammation is described in cellular and molecular detail, as is corticosteroid resistance in chronic obstructive pulmonary disease and the mechanisms of histone deacetylase reduction in the disease. Interference with specific signal pathways is an attractive therapeutic option, according to the author, and theophylline is one molecule that in low concentrations can restore histone deacetylase activity. New therapeutic targets are antioxidants; new theophylline derivatives; curcurin, a polyphenol found in curry powder; macrolides; and as yet elusive histone deacetylase activators.
Myeloid malignancies, including acute myeloid leukemia and the myelodysplastic syndrome, are discussed in Chap. 15, by Lauren C. Suarez and Steven D. Gore. Similar to other malignancies, myelodysplastic syndromes exhibit chromosomal abnormalities and mutations. In addition, epigenetic modifications such as DNA methylation play a prominent role both in the acute disease and in the yelodysplastic syndrome, its precursor lesion. The results of pilot studies on the effects of azacitidine, a DNA methyltransferase inhibitor, are discussed in terms of dosage and treatment cycles. Parallel studies with decitabine, an azacitidine congener, are analyzed and compared with azacitidine studies. The authors then raise the question whether these two agents act through epigenetic mechanisms and from their evaluation of clinical studies think that changes in epigenetic profiles may be linked to treatment response and thus constitute a response indicator. The role of histone deacetylase inhibitors is then taken up, with discussion of short chain fatty acids, benzamides, and romidepsin. Other histone deacetylase inhibitors such as hydroxamic acids (vorinostat, panobinostat, belinostat) are evaluated. The authors then raise the question about combining epigenetic drugs and discuss studies that have dealt with this important therapeutic approach. The chapter concludes with an analysis of the future of epigenetic therapies in the treatment of the myelodysplastic syndrome.
Study of the epigenome has over recent years become an important field of research and insights are finding increasing application in medical science and practice. We are grateful to the authors for their willingness to share their knowledge and experience with a wider professional audience, thereby reinforcing the link between developing knowledge and its practical application, at the same time emphasizing the as yet wide gap between promise and therapy. We also thank Springer, our publisher, for their help in assuring the intellectual and aesthetic quality of this treatise.

Helmtrud I. Roach
Felix Bronner
Southampton, UK Richard O.C. Oreffo

1 Epigenetics and Chronic Diseases: An Overview
2 Techniques to Study DNA Methylation and Histone Modification
3 Mechanisms of Epigenetic Gene Silencing
4 Mechanisms of Epigenetic Gene Activation in Disease: Dynamics of DNA Methylation and Demethylation
5 The Role of Histone Demethylases in Disease
6 Autoimmune Diseases
7 Epigenetics of Rheumatoid Arthritis
8 DNA Methylation Changes in Osteoarthritis
9 Epigenetics and Type 2 Diabetes
10 Epigenetic Regulation of Asthma and Allergic Diseases
11 Epigenetics in Psychiatry
12 Epigenetics and Late-Onset Alzheimer's Disease
13 Epigenetic Mechanisms in the Developmental Origins of Adult Disease
14 Targeting Histone Deacetylases in Chronic Obstructive Pulmonary Disease
15 Clinical Trials of Epigenetic Modifiers in the Treatment of Myelodysplastic Syndrome

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