Epigenetics in Human Disease

Trygve O Tollefsbol, Trygve Tollefsbol, Trygve O. Tollefsbol

• Publisher: Academic Press
• Year: 2018
• Edition: 2
• eBook ISBN:
  9780128123294
• Topic: Medicine
• Subtopic: Genetics in Medicine

Epigenetics in Human Disease, Second Edition examines the diseases and conditions on which we have advanced knowledge of epigenetic mechanisms, such as cancer, autoimmune disorders, aging, metabolic disorders, neurobiological disorders and cardiovascular disease. In addition to detailing the role of epigenetics in the etiology, progression, diagnosis and prognosis of these diseases, novel epigenetic approaches to treatment are also explored. Fully revised and up-to-date, this new edition discusses topics of current interest in epigenetic research, including stem cell epigenetic therapy, bioinformatic analysis of NGS data, and epigenetic mechanisms of imprinting disorders. Further sections explore online epigenetic tools and datasets, early-life programming of epigenetics in age-related diseases, the epigenetics of addiction and suicide, and epigenetic approaches to regulating and preventing diabetes, cardiac disease, allergic disorders, Alzheimer's disease, respiratory diseases, and many other human maladies. - Includes contributions from leading international investigators involved in translational epigenetic research and therapeutic applications - Integrates methods and applications with fundamental chapters on epigenetics in human disease, along with an evaluation of recent clinical breakthroughs - Presents side-by-side coverage of the basis of epigenetic diseases and treatment pathways - Provides a fully revised resource covering current developments, including stem cell epigenetic therapy, the bioinformatic analysis of NGS data, epigenetic mechanisms of imprinting disorders, online epigenetic tools and datasets, and more

Section VII

Other Disoders/Diseases

Outline

1. Chapter 18. Epigenetic-Processes Driven Disorders and Therapeutics
2. Chapter 19. Epigenetics of Allergic Diseases Allergies, Eczema, Asthma, and Rhinitis
3. Chapter 20. Epigenetic Treatment Approaches to Cardiovascular Disease
4. Chapter 21. Epigenetics and Human Infectious Diseases
5. Chapter 22. Therapy of Infectious Diseases Using Epigenetic Approaches
6. Chapter 23. Translational Aspects of the Endometriosis Epigenome
7. Chapter 24. Aberrant DNA Methylation Patterns in Gynecologic Cancers: Implications for Prevention and Therapy
8. Chapter 25. Epigenetics in Human Reproduction and Gynecologic Diseases

Chapter 18

Epigenetic-Processes Driven Disorders and Therapeutics

Sravya Thumoju¹, and Vasavi Mohan^{1,2 1}Vasavi Medical and Research Centre, Hyderabad, India ²Hansgene Cancer Foundation, Hyderabad, India

Abstract

Scientific research directed at understanding epigenetic aspects of human disease has just begun reaping results with an applicative potential to be used for therapeutic intervention. Epigenetic alterations such as methylation, histone changes, and RNA-associated gene regulation play a major role in the structuring of a certain orderly functioning of the human body systems. Some of these mechanisms determine the individuals' fate right from the time of conception and actually even earlier. The relevance of noncoding genome to the existence and functioning of an organism is slowly unfurling, along with the realization of the existence of an epigenetic memory with transgenerational inheritance. We address these topics that are fundamental to exploiting epigenetic mechanisms for appropriate disease management and treatment.

Keywords

Epigenetics; Gene regulation; Human disease; Management; Therapeutic

Chapter Outline

1. 18.1 What Is Epigenetics?
2. 18.2 Introduction
   1. 18.2.1 DNA Methylation
   2. 18.2.2 Histone Modifications
   3. 18.2.2.1 Histone Acetylation, Histone Phosphorylation, Histone Methylation
   4. 18.2.3 RNA-Associated Silencing
3. 18.3 Epigenetics and Environment
   1. 18.3.1 Nutrition and Metabolomics
   2. 18.3.2 During Development
   3. 18.3.3 Microbiome
   4. 18.3.4 Pollutants
4. 18.4 Epigenetics in Human Diseases
   1. 18.4.1 Cardiovascular Diseases
   2. 18.4.2 In Cancer
   3. 18.4.3 Imprinting Disorders
   4. 18.4.4 Pediatric Disorders
   5. 18.4.5 Immunity
   6. 18.4.6 Neuropsychiatric/Neurodevelopmental Disorders
   7. 18.4.7 Aging
5. 18.5 Conclusion
6. References
7. Further Reading

18.1. What Is Epigenetics?

Epigenetics is the study of how expression of genes can be changed, without changing the sequence of DNA itself. Knowledge of genetic changes alone will not give us a complete solution to understand the enigma of human disease; epigenomic regulation directed by the intrinsic and extrinsic environment of the cell will need to be comprehended. Major epigenetic mechanisms include DNA methylation and demethylation reactions, chromatin restructuring, and regulation of gene expression via noncoding RNAs (ncRNAs) [1]. A know-how of what causes disease is essential not only to arrive at suitable treatments but also to work toward ways of preventing disease in the first place. This chapter deals with various epigenetic phenomenon in play, to maintain normal homeostasis and their variations which are responsible for disease of different organs in the human system.

18.2. Introduction

Epigenetics comprises of the stable and heritable (or potentially heritable) changes in gene expression that do not involve a change in the base sequence of DNA [2]. This cellular machinery is responsible for remotely regulating the expression of genes. Like mutations give rise to an abnormal gene functioning and its pathological effect, epimutations can give rise to epigenetic phenotypes obvious in loss of imprinting disorders. Technological advancements have given a boost to the increasing interest in the epigenetic regulation of the “blueprint of life.”

Epigenetic study now allows the mapping of epigenetic marks, such as DNA methylation, histone modifications, and nucleosome positioning, which are critical for regulating genes and for ncRNA expression. There are also genetic disorders where the chromatin structure and remodeling are affected [3]. These disorders can affect chromatin in trans or in cis, as well as the expression of both imprinted and nonimprinted genes. The characterization of a human DNA methylome at single-nucleotide resolution, the discovery of the CpG island shores, the finding of new histone variants and modifications, and the unveiling of genome-wide nucleosome-positioning maps highlight the accelerating speed of epigenomic research over the past decade or so. We are now capable of exploring how aberrant placement of these epigenetic marks and mutations in the epigenetic machinery are involved in disease.

Within cells, there are essentially three systems that can interact with each other to silence/affect gene expression: DNA methylation, histone modifications, and RNA-associated silencing.

18.2.1. DNA Methylation

DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular processes. These include embryonic development, transcription, chromatin structuring, X chromosome inactivation, genomic imprinting, and maintaining chromosome stability. Consistent with these important roles, a growing number of human diseases have been found to be associated with aberrant DNA methylation. The study of these diseases has provided new and fundamental insights into the role that DNA methylation and other epigenetic modifications have, in development and normal cellular homeostasis [4]. Although methylation works to modify the nucleosomes and silence the chromatin, there are other important epigenetic processes that affect gene expression. DNA methylation is an epigenetic mechanism in which the methyl group is covalently coupled to the C5 position of the cytosine residue of CpG dinucleotides. Presence of methyl groups at these positions does not allow access to transcription factor binding, and hence there is cessation of gene expression (Fig. 18.1). DNA methylation at gene promoters generally leads to gene silencing and is catalyzed by a group of enzymes known as DNA methyltransferases (DNMTs). During development, the epigenome undergoes waves of demethylation and methylation changes. As a result, there are cell type/tissue-specific DNA methylation patterns.

Figure 18.1 DNA methylation is linked to the regulation of gene expression, where methylation in promoter regions of genes or intragenic methylation, as observed in invertebrates, silences the expression of those genes. Inaccessibility of DNA regulatory elements to their transcription factors is due to the methyl moieties at CpG residues, eventually suppressing transcription.

18.2.2. Histone Modifications

18.2.2.1. Histone Acetylation, Histone Phosphorylation, Histone Methylation

For a compact chromatin to be able to express itself by allowing interaction with other molecules, histone modifications play an important role and can be transferred as an epigenetic mark to the daughter cells. Histones are methylated on their lysine or arginine residues by histone MTases, which use S-adenosyl methionine (SAM) as the methyl donor. Depending on the type and position of the residues methylated, they either promote or repress transcription [5]. Each of the residues may be methylated more than once, signaling a different outcome to the chromatin. Acetylation targets lysine residues in the aminoterminal tails of core histone proteins. This process does not permit the nucleosome array to fold further and helps in chromatin decondensation. This gives access to the various transcription factors, their cofactors, polymerases, etc. for active transcription from the genes (Fig. 18.2). Elevated glycolysis in cancer is associated with global histone hyperacetylation. Inhibition of glycolysis holds promise for modulating histone acetylation. Therefore, like methylation, acetylation process is another epigenetic mechanism by which g...

Table of contents

• Cover image
• Title page
• Table of Contents
• Translational Epigenetics Series
• Copyright
• List of Contributors
• Preface
• Section I. Introduction
• Section II. Methodology
• Section III. Human Cancer
• Section IV. Neurological Disease
• Section V. Autoimmune Disease
• Section VI. Metabolic Disorders
• Section VII. Other Disoders/Diseases
• Section VIII. Development, Aging and Transgenerational Effects
• Section IX. Future Research
• Index