Transgenerational Epigenetics

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• Publisher: Academic Press
• Year: 2019
• ISBN:
  9780128167335
• Edition: 2
• Topic: Biological Sciences
• Subtopic: Genetics & Genomics
• Index: Biological Sciences

Transgenerational Epigenetics, Second Edition, offers the only up-to-date, comprehensive analysis of the inheritance of epigenetic phenomena between generations with an emphasis on human disease relevance, drug discovery, and next steps in clinical translation. International experts discuss mechanisms of epigenetic inheritance, its expression in animal and plant models, and how human ailments, such as metabolic disorders and cardiovascular disease are influenced by transgenerational epigenetic inheritance. Where evidence is sufficient, epigenetic clinical interventions are proposed that may help prevent or reduce the severity of disease before offspring are born.

This edition has been thoroughly revised in each disease area, featuring newly researched actors in epigenetic regulation, including long noncoding RNA in addition to histone modifications and DNA methylation. Therapeutic pathways in treating cancer and extending human longevity are also considered, as are current debates and future directions for research.

• Presents a fully-updated and expanded release addressing transgenerational epigenetics, epigenetic mechanisms of gene regulation, and the role of epigenetics in human longevity and cancer
• Examines the field from "bench-to-bedside", discussing basic science, disease management, current debates, and next steps in epigenetic research and drug discovery
• Features chapter contributions from international experts

Chapter 1

Generational epigenetic inheritance

Trygve O. Tollefsbol ^{1 , 2 , 3 , 4 , 5 , 6 1} Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States ² Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States ³ Comprehensive Center for Healthy Aging, University of Alabama at Birmingham, Birmingham, AL, United States ⁴ Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL, United States ⁵ Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, United States ⁶ University Boulevard, Birmingham, Birmingham, AL, United States

Abstract

Variations in the expression of genetic information are often mediated by epigenetic mechanisms that lead to phenotypic changes. Epigenetic states are inherited from one cell to another through mitotic cellular divisions, although much of the epigenetic information encoded in the genome is reset during reproduction of an organism. Because epigenetic erasure of the parental epigenome is not complete, meiotic epigenetic transfer of information may allow for phenotypic traits to appear in subsequent generations, a process referred to as transgenerational epigenetics. The epigenetic information, often established by mechanisms such as DNA methylation, histone modifications, and noncoding RNA, may not only influence gene expression in the first generation of offspring but may also persist for multiple generations. Additionally, generational epigenetic transfer has been implicated in many different medical disorders such as those of a metabolic nature. Clinical intervention in disorders of generational epigenetic inheritance is rapidly developing and could provide significant advances in managing heritable disorders or diseases that have been relatively recalcitrant to more conventional approaches to therapy.

Keywords

DNA methylation; Epigenetic inheritance; Histone modification; Inheritance; Noncoding RNA; Transgenerational

1. Introduction
2. Definitions and history of generational epigenetic inheritance
3. Germ line epigenetics
4. Parental epigenetic inheritance
5. Basic mechanisms/processes of epigenetic inheritance
6. Model organisms
7. Evolution of transgenerational epigenetics
8. Environmental epigenetic effects on the offspring
9. Impact of transgenerational epigenetics on disease
10. Clinical significance of transgenerational epigenetics
11. Conclusion
12. References

Introduction

With the rapid development of molecular tools that delineate and monitor epigenetic processes, especially with respect to changes in the epigenome, the more traditional and general definition of epigenetics as heritable changes that influence gene expression without a change in the DNA sequence is in need of expansion and revision. It is now apparent that the influence of epigenetic information carried out by a myriad of processes such as DNA methylation, histone modifications, and noncoding RNA is not only limited to mitotic cell-to-cell inheritance but also extended to meiotic generational inheritance. This needs to be distinguished in the definition of epigenetics. Therefore, a more modern definition of epigenetics is the modification of phenotypic traits that can be inherited mitotically during cell division and meiotically during transgenerational reproduction without changes in DNA sequence. Through this revised definition, epigenetic inheritance distinguishes between mitotic and meiotic transfer of information not encoded in the DNA sequence. Transgenerational epigenetics, as an important and distinct form of epigenetic inheritance, refers specifically to transmittance of information other than what is encoded in the DNA sequence from an organism to its offspring and potentially to subsequent generations of the offspring. It seems highly feasible that although epigenetic inheritance and transgenerational epigenetics share many common mechanisms, unique mechanisms may exist during generational epigenetic transfer that are not found in classical mitotic epigenetic inheritance. Therefore, transgenerational epigenetics needs to be separately noted in the definition of epigenetic inheritance as specified above.

Natural selection, initially put into publication-ready format by Alfred Russel Wallace and later by Charles Darwin, is not necessarily in conflict with transgenerational epigenetics and in fact Darwin's Origin of Species did not mitigate the possibility of a variant of Lamarckism as a mechanism that contributes to inheritance. Lamarckism, named after Jean-Baptiste Lamarck, refers to lifetime characteristics of an organism that can be inherited by its offspring. Transgenerational epigenetics has been suggested to be Lamarckian in nature in that evidence has been posited that epigenetic phenomena such as DNA methylation and chromatin changes that can control gene expression may be responsive to environmental stimuli resulting in phenotypic changes that persist for multiple generations [1–4]. If epigenetic marks were completely erased with each new generation, as was originally thought by some, Lamarckian epigenetic inheritance would not be feasible. However, there is now ample evidence that the erasure of epigenetic marks is not complete at some loci and that epigenetic changes that are acquired during the life span of an organism can be transferred to subsequent generations as generational epigenetic inheritance [5–9].

Although further evidence is needed to more fully establish the nature and mechanisms of transgenerational epigenetics, mounting evidence suggests that generational epigenetic inheritance influences not only key phenotypic traits of offspring but that it also has an impact on a number of human disorders and diseases. Many clinically relevant disorders such as metabolic diseases are likely affected by generational epigenetic inheritance, and future studies directed toward elucidating the epigenetic mechanisms contributing to heritable diseases as well as potential therapeutic intervention will be of considerable interest [10].

Definitions and history of generational epigenetic inheritance

Due in part to the fact that this is still a relatively young science, one of the most debated topics in the area of generational epigenetic inheritance is the basic definition of transgenerational epigenetics itself. Perhaps the most liberal interpretation of this term presupposes that an epigenetic change in one generation (F0) that is transferred to the next generation (F1) or even to subsequent generations (e.g., F2, F3, etc.) would qualify as a transgenerational epigenetic inheritance. Some even loosely group into this more liberal interpretation maternal epigenetic effects during pregnancy that appear in the fetus regardless of whether they are carried through the germ line. An example of this may be varied effects on the fetus due to maternal consumption of specific dietary components that impact epigenetic processes such as DNA methylation or histone modification. One could posit that these epigenetic effects are transgenerational in nature in the sense that the behavior of the F0 generation (e.g., dietary consumption by the pregnant mother) is being transferred through epigenetic modifications to the fetus as the F1 generation. However, this phenomenon may not have any impact on the germ line and would therefore be more appropriately referred to, at least in mammals, as transplacental epigenetic effects rather than true transgenerational effects as is usually imagined when this term is used. That does not at all imply, however, that transplacental or parent to offspring epigenetic effects that bypass the germ line are not also of great importance and do not have a place among discussions of generational epigenetic inheritance. Given that these effects may be transferred epigenetically from one generation to another even if not necessarily through the germ line, it seems that they are of great relevance to the topic, and therefore this book has not excluded discussion of these more liberal interpretations. Thus, epigenetic transfer of information from the parent to the offspring, even if through environmental effects not encoded in the germ line, may have great medical importance.

The more exacting albeit conservative interpretation of transgenerational epigenetic inheritance excludes transplacental epigenetic effects not affecting the germ line, and this definition is the most accurate and appropriate when strictly discussing transgenerational epigenetics although this is subject to debate. Michael Skinner, a leading authority in the field of transgenerational epigenetics, along with his colleagues, Eric Nilsson and Millissia Ben Maamar, delineates very clearly in Chapter 2 the prevailing definition of transgenerational epigenetic inheritance as epigenetic information mediated through the germ line between generations that contributes to variation in phenotype. This definition excludes transplacental and/or non–germ line environmental influences. As aforementioned, however, even if this more strict definition of transgenerational epigenetic inheritance is the one that should be used and that is the most accurate, other epigenetic effects that can be transmitted from one generation to another are also of great interest to medical science. Other significant contributions of Chapter 2 include the concept of germ line epimutations that mediate a transgenerational phenotype as well as the role of the environment on epigenetic transgenerational inheritance. In addition, several fascinating contributions of Michael Skinner's laboratory and other leading laboratories that are focused on transgenerational epigenetic inheritance are reviewed in Chapter 2.

Even though the definition of transgenerational epigenetic inheritance is subject to debate, few would deny the controversial history of Lamarckism, which emphasized individual interaction with the environment as an important component of heredity and evolution. Although Lamarck's theory of evolution is too often viewed as in conflict with natural selection as a driving force of evolution, Chapter 3 details the history of the development of these theories and makes the important point that Darwin was an advocate of Lamarck's general theory of evolution and that he realized that Lamarckian acquired traits likely also serve as an evolutionary mechanism. Unfortunately, Lamarckian evolution later received considerable opposition, and it has only been within the last few decades that Lamarckism has been resurrected, due in large part to the evidence of transgenerational epigenetic inheritance. The gene-centric dogma of heredity and evolution is slowly giving way to more encompassing concepts that are not limited to an organism but include the organism as part of a dynamic environment that is constantly modifying numerous epigenetic processes including those that extend beyond the gene itself.

Germ line epigenetics

It has now generally accepted that genetic information can be epigenetically reprogrammed in both the maternal germ line and the paternal germ line and that this may lead to inherited phenotypic changes in the offspring, although how vast these modifications extend and how often this occurs are still subjects of considerable investigation and is an area of great need of further study.

Besides maternal germ line epigenetic changes that are well known to contribute to generational epigenetic inheritance, paternal germ line epigenetic changes are also important contributing factors in the manifestation of generational epigenetic inheritance. Epigenetic events may occur during many different stages of gametogenesis, but one stage that is often overlooked is the major epigenetic reprogramming that occurs during fertilization with protamine removal, histone replacement, and initiation of partial erasure of DNA methylation. However, the spermiogenesis phase following meiosis and characterized by differentiation and maturation of male germ cells is the most dramatic phase occurring in male germ cells, at least with respect to epigenetic events that may be heritable to offspring. Increasing evidence has indicated that epigenetic processes occurring in...

Table of contents

• Cover image
• Title page
• Table of Contents
• Translational Epigenetics Series
• Copyright
• List of contributors
• Preface
• Chapter 1. Generational epigenetic inheritance
• Section I. Definitions and history of generational epigenetic inheritance
• Section II. Germline epigenetics
• Section III. Parental epigenetic inheritance
• Section IV. Basic mechanisms/processes of epigenetic inheritance
• Section V. Model organisms
• Section VI. Evolution of transgenerational epigenetics
• Section VII. Environmental epigenetic effects on the offspring
• Section VIII. Impact of transgenerational epigenetics on disease
• Section IX. Clinical significance of transgenerational epigenetics
• Index