Epigenetics is considered by many to be the "new genetics" because the realization that many biological phenomena are controlled not through gene mutations, but rather through reversible and heritable epigenetic processes that have opened up new paths for discovery. The biological processes impacted by epigenetics range from tissue/organ regeneration, X-chromosome inactivation, and stem cell differentiation to genomic imprinting and aging. The effects of epigenetics are vast and encompass lower organisms as well as humans. Aberrations of epigenetics influence many diseases involving but not limited to cancer, immune disorders, neurological and metabolic disorders, and imprinting diseases. Clinical intervention is already in place for some of these disorders and many novel epigenetic therapies are on the horizon.
This comprehensive collection of reviews written by leaders in the field of epigenetics provides a broad view of this important and evolving topic. From molecular mechanisms and epigenetic technology to discoveries in human disease and clinical epigenetics the nature and applications of the science will be presented for those with interests ranging from the fundamental basis of epigenetics to therapeutic interventions for epigenetic-based disorders.
• Contributions by leading international investigators involved in molecular research and clinical and therapeutic applications
• Integrates methods and biological topics with basic and clinical discoveries
• Includes coverage of new topics in epigenetics such as prions, regulation of long-term memory by epigenetics, metabolic aspects of epigenetics, and epigenetics of neuronal disorders
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About the Author
Professor of Biology, University of Alabama at Birmingham, Birmingham, AL. Dr. Tollefsbol is a Professor of Biology and a Senior Scientist in the Center for Aging, Comprehensive Cancer Center, Nutrition Obesity Research Center, and the Comprehensive Diabetes Center at the University of Alabama at Birmingham (UAB). He is Director of the UAB Cell Senescence Culture Facility which he established in 1999 and a Steering Committee Member of the UAB Center for Aging. Dr. Tollefsbol trained as a Postdoctoral Fellow and Assistant Research Professor with members of the National Academy of Science at Duke University and the University of North Carolina. He earned doctorates in molecular biology and osteopathic medicine from the University of North Texas Health Sciences Center and his bachelor’s degree in Biology from the University of Houston. He has received prior funding from the NIA, NCI, NHLBI, NIMH and other federal institutes as well as the Glenn Foundation for Medical Research, Susan G. Komen for the Cure, the American Federation for Aging Research (AFAR), and the American Institute for Cancer Research (AICR) among many other sources. The Glenn Foundation for Medical Research funding was unsolicited and was awarded to Dr. Tollefsbol for lifetime contributions to the field of aging. In 2006 Dr. Tollefsbol was selected and highlighted as part of the 25th anniversary of the AFAR for significant contributions to aging research. Dr. Tollefsbol’s research interests have covered a wide range of topics such as aging, epigenetics, nutrition, cancer, telomerase, and caloric restriction. Work from his laboratory has been featured in Women’s Health magazine, Shape magazine, and the AICR Newsletter and Dr. Tollefsbol has been a Scientist in the Spotlight in ScienceNow. Currently he serves as an Associate Editor for Frontiers in Epigenomics and is on the Editorial Boards of the international journals Open Longevity Science, Epigenetics of Diabetes and Obesity, Molecular Biotechnology and Clinical Epigenetics. He is also a contributing Editor of Lewin’s GENES X classic textbook. Over 25 of the publications from Dr. Tollefsbol’s laboratory have received national or international accolades such as best paper award, selection for press release by the journal editors and featured on the journal homepage. Dr. Tollefsbol has been invited to give presentations on his research in many countries including Germany, China, Italy, Switzerland, France and The Netherlands as well as at various leading institutions in the US such as Harvard Medical School, Tufts University and the University of California at San Francisco. His research has received considerable media attention both nationally and internationally through television, newspaper and radio venues and has been highlighted in eScience News and ScienceDaily. He has ten books which have been published or are in progress and a recent book on “Epigenetics of Aging” that Dr. Tollefsbol co-authored and edited was highlighted in Nature.
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Handbook of EpigeneticsThe New Molecular and Medical Genetics
By Trygve Tollefsbol
Academic PressCopyright © 2011 Elsevier Inc.
All right reserved.
Chapter OneEpigenetics: The New Science of Genetics
Trygve O. Tollefsbol
The term epigenetics was first introduced in 1942 by Conrad Waddington and was defined as the causal interactions between genes and their products that allow for phenotypic expression. This term has now been somewhat redefined and although there are many variants of the definition of this term today, a consensus definition is that epigenetics is the collective heritable changes in phenotype due to processes that arise independent of primary DNA sequence. This heritability of epigenetic information was for many years thought to be limited to cellular divisions. However, it is now apparent that epigenetic processes can be transferred in organisms from one generation to another. This phenomenon was first described in plants and has been expanded to include yeast, Drosophila, mouse and, possibly, humans.
THE BASICS OF DNA METHYLATION AND HISTONE MODIFICATIONS
In most eukaryotes DNA methylation, the most studied of epigenetic processes, consists of transfer of a methyl moiety from S-adenosylmethionine (SAM) to the 5-position of cytosines in certain CpG dinucleotides. This important transfer reaction is catalyzed by the DNA methyltransferases (DNMTs). The three major DNMTs are DNMT1, 3A and 3B and DNMT1 catalyzes what is referred to as maintenance methylation that occurs during each cellular replication as the DNA is duplicated. The other major DNMTs, 3A and 3B, are known more for their relatively higher de novo methylation activity where new 5-methylcytosinesare introduced in the genome at sites that were not previously methylated. The most significant aspect of DNA methylation, which can also influence such processes as X chromosome inactivation and cellular differentiation, is its effects on gene expression. In general, the more methylated a gene regulatory region, the more likely it is that the gene activity will become down-regulated and vice versa although there are some notable exceptions to this dogma. Chapter 2 of this book reviews the mechanisms of DNA methylation, methyl-CpG recognition and demethylation in mammals. Recent advances have highlighted important roles of UHRF1 and DNMT3L that are required for maintenance and de novo methylation, respectively, and the potential inclusion of 5-hydroxymethylcytosine with 5-methylcytosine in expressing the impact of DNA methylation on the genome.
Chromatin changes are another central epigenetic process that have an impact not only on gene expression, but also many other biological processes. Posttranslational modifications of histones such as acetylation and methylation occur in a site-specific manner that influences the binding and activities of other proteins that influence gene regulation. The histone acetyltransferases (HATs) catalyze histone acetylation and the histone deacetylases (HDACs) result in removal of acetyl groups from key histones that comprise the chromatin. These modifications can occur at numerous sties in the histones and are most common in the amino terminal regions of these proteins as reviewed in Chapter 3. In general, increased histone acetylation is associated with greater gene activity and vice versa. By contrast, methylation of histones has variable effects on gene activity where lysine 4 (K4) methylation of histone H3 is often associated with increasing gene activity whereas methylation of lysine 9 (K9) of histone H3 may lead to transcriptional repression. There is also considerable crosstalk between DNA methylation and histone modifications  such that cytosine methylation may increase the likelihood of H3-K9 methylation and H3-K9 methylation may promote cytosine methylation.
ADDITIONAL EPIGENETIC PROCESSES
Among the most exciting advances in epigenetics have been the discoveries that many other processes besides DNA methylation and histone modifications impact the epigenetic behavior of cells. For instance, non-coding RNA (Chapter 4) including both short and long forms, often share protein and RNA components with the RNA interference (RNAi) pathway and they may also influence more traditional aspects of epigenetics such as DNA methylation and chromatin marking. These effects appear to be widespread and occur in organisms ranging from protists to humans. Prions are fascinating in that they can influence epigenetic processes independent of DNA and chromatin. In Chapter 5 it is shown that structural heredity also is important in epigenetic expression where alternative states of macromolecular complexes or regulatory networks can have a major effect on phenotypic expression independent of changes in DNA sequences. The prion proteins are able to switch their structure in an autocatalytic manner that can not only influence epigenetic expression, but also lead to human disease. The position of a gene in a given chromosome can also greatly influence its expression (Chapter 6). Upon rearrangement, a gene may be relocated to a heterochromatic region of the genome leading to gene silencing and many other gene position effects have been described, some of which may also lead to various human diseases. Polycomb mechanisms are another relatively new aspect of epigenetics that control all of the major cellular differentiation pathways and are also involved in cell fate. Polycomb repression is very dynamic and can be easily reversed by activators and they also raise the threshold of the signals or activators required for transcriptional activation which places these fascinating proteins within the realm of epigenetic processes (Chapter 7). Therefore, although DNA methylation and histone modifications are mainstays of epigenetics, recent advances have greatly expanded the epigenetic world to include many other processes such as non-coding RNA, prions, chromosome position effects and Polycomb mechanisms.
Many of the advances in epigenetics that have driven this field for the past two decades can be traced back to the technological breakthroughs that have made the many discoveries possible. We now have a wealth of information about key gene-specific epigenetic changes that occur in a myriad of biological processes. In Chapter 8, gene-specific techniques for determining DNA methylation are reviewed. These methods include bisulfite sequencing, methylation-specific PCR (MSP) and quantitative MSP. These techniques can be applied not only to mechanisms of epigenetic gene control, but to diagnostic processes as well. In addition, there have been important breakthroughs in analyses of the methylome at high resolution. Microarray platforms and high-throughput sequencing have made possible new techniques to analyze genome-wide features of epigenetics that are based on uses of methylation-sensitive restriction enzymes, sodium bisulfite conversion and affinity capture with antibodies or proteins that select methylated DNA sequences. Techniques such as restriction landmark genomic sequencing (RLGS), methylation-sensitive restriction fingerprinting, methylation-specific digital karyotyping, targeted and whole genome bisulfite sequencing, methylated DNA immunoprecipitation (MeDIP) and the methylated-CpG island recovery assay are reviewed in Chapter 9. Mechanisms for lysine 9 methylation of histone H3 are reviewed in Chapter 10 and chromatin immunoprecipitation (ChIP) and chromosome conformation capture (3C) are covered in Chapter 11. The 3C-based method allows analyses of the spatial proximity of distant functional genomic sites to render a three dimensional view of the genome within the nucleus itself. Since there has been much information derived from epigenomic approaches, methods to analyze data from ChIP-on-chip and ChIPseq, for example, are becoming increasingly important and are delineated in Chapter 12. There is no question that developments in the tools for assessing epigenetic information have been and will continue to be important factors in advancing epigenetics.
MODEL ORGANISMS OF EPIGENETICS
Epigenetic processes are widespread and much of our extant knowledge about epigenetics has been derived from model systems, both typical and unique. The ease of manipulation of eukaryotic microbes has facilitated discoveries in the molecular mechanisms of basic epigenetic processes (Chapter 13). In these cases epigenetics may play a key role in genomic protection from invasive DNA elements and in identifying the importance of gene silencing mechanisms in evolution. Drosophila is a mainstay model in biology in general and the epigenetics field is not an exception in this regard. For example, Chapter 14 offers a number of examples of transgenerational inheritance in Drosophila and this model system also shows promise in unraveling the evolutionary aspects of epigenetics. Probably the most useful model system in epigenetics to date is the mouse model (Chapter 15). Randy Jirtle and colleagues review numerous different mouse models that are important in many epigenetic processes such as transgenerational epigenetics and imprinting and these models have potential in illuminating human diseases such as diabetes, neurological disorders and cancer. Plant models (Chapter 16) are of great importance in epigenetics due in part to their plasticity and their ability to silence transposable elements. RNAi silencing in plants has been at the forefront of epigenetics and plant models will likely lead the way in several other epigenetic processes in the future. Thus, model development, like the advances in techniques, have made many of the most exciting discoveries in epigenetics possible for a number of years.
METABOLISM AND EPIGENETICS
Epigenetics is intricately linked to changes in the metabolism of organisms and these two processes cannot be fully understood separately. S-adenosylmethionine (SAM) is a universal methyl donor and drives many epigenetic processes (Chapter 17) and the importance of SAM in epigenetic mechanisms is vast. Metabolic functions can also influence the chromatin which is a major mediator of epigenetic processes (Chapter 18). It is now apparent that various environmental influences and metabolic compounds can regulate the many enzymes that modify histones in mammals. Thus, metabolic processes impact DNA methylation and chromatin remodeling, the two major epigenetic mediators, and it is likely that this relatively new field will continue to advance in an exponential manner.
FUNCTIONS OF EPIGENETICS
The functions of epigenetics are indeed numerous and it would be next to impossible to do complete justice in one book to this ever-expanding field. However, Chapters 19–25 illustrate a few of the many different functions that epigenetics mediates. Stem cells rely in part on signals from the environment and epigenetic mechanisms such as DNA methylation, histone modification, and microRNA (miRNA) have central roles in how stem cells respond to environmental influences (Chapter 19). Regenerative medicine is dependent upon stem cells and skeletal muscle regeneration (Chapter 20) involves key changes in the epigenome that regulate gene expression in muscle progenitors through chromatin as well as microRNA epigenetic changes. It has been known that epigenetics is important in X chromosome inactivation for quite some time although advances in this area are continuing to move rapidly. It is now apparent that X chromosome inactivation is regulated not only through the genes Tsix and Xist, but also pluripotency factors that affect Xist expression (Chapter 21). Genomic imprinting, likewise, has been known to be epigenetic-based for many years, but discoveries in this area of epigenetics continue to move at a rapid pace. Genomic imprinting is not limited to mammals but also occurs through analogous processes in plants and invertebrates and it can occur in specific tissues or during critical developmental stages (Chapter 22). Profound new discoveries have recently occurred in the area of the epigenetics of memory processes. Recent exciting discoveries have shown that gene regulation through epigenetic mechanisms is necessary for changes in adult brain function and behavior based on life experiences (Chapter 23). Moreover, new drugs that impact epigenetic mechanisms may have future uses in treating or alleviating cognitive dysfunction. Transgenerational inheritance (Chapter 24) is also a form of memory based in part on epigenetics in that early life experiences that impact epigenetic markers can greatly influence adult health and risk for diseases. In addition, the aging process is a form of epigenetic memory and experience, in that our genes are epigenetically modified from our parents and also during our entire life spans, that can significantly impact the longevity of humans as well as our risk for the numerous age-related diseases, many of which are also epigenetically-based (Chapter 25). It is therefore apparent that epigenetics influences a number of different functions and it is highly likely that many additional functions of epigenetics will be discovered in the future.
Although many think of epigenetic processes as being inherent and static to a specific organism, it is apparent that epigenetics has been a major force behind the evolutionary creation of new species. Chapter 26 reveals that epigenetic mechanisms have a major influence on mutations. The evolutionary impact of epigenetics is in full force even today with the ever-changing environment that can modulate gene expression through epigenetic processes. For example, rapid changes in diet and the modern lifestyle as well as environmental pollution are undoubtedly impacting not only the human epigenome, but also the evolution of many of the more primitive species that in turn greatly affect the environment.
Dietary factors are highly variable not only between individuals, but also among human populations and various nonhuman species. Many studies have shown that diet has a profound effect on the epigenetic expression of the genome and therefore on the phenotype. DNA methylation is the epigenetic process that has been most often associated with diet and changes in the diet may not only induce varying epigenetic expressions, but, paradoxically, a changed diet may also transfix epigenetic changes that can then be transferred to the next generation in a stable manner (Chapter 27). Environmental agents other than diet also impact the epigenome. For example, Chapter 28 reviews the many environmental agents that can lead to alterations in the epigenome thereby inducing toxicity or carcinogenesis. Moreover, invasion by foreign agents can influence the epigenome (Chapter 29). Viruses and bacteria, for example, play a major role in altering the epigenetic expression of the genome and these processes may lead to human diseases such as cancer. Chapter 30 by Walter Doerfler and colleagues illustrates details of the role of adenovirus type 12 (Ad12) in reshaping the hamster genome and they also provide analyses of the human FMR1 promoter that is impacted by DNA methylation in the fragile X syndrome. Drugs also reshape the epigenome, which has opened the new field of pharmacoepigenomics. It is clear that certain populations respond differently to drugs and much of this variation may be explained by epigenetic factors (Chapter 31). Thus, epidemiological factors have great importance in epigenetics and this is influenced by diet, environmental agents, infections, drugs and likely many other factors as well.
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Table of Contents
1. Epigenetics: The New Science of Genetics
SECTION I: Molecular Mechanisms of Epigenetics
2. Mechanisms of DNA Methylation, Methy-CpG Recognition, and Demethylation in Mammals
3. Mechanisms of Histone Modifications
SECTION II: Additional Epigenetic Processes
4. The Epigenetics of Non-coding RNA
5. Prions and Prion-like Phenomena in Epigenetic Inheritance
6. Chromosomal Position Effects and Gene Variegation: Impact in Pathologies
7. Polycomb Mechanisms and Epigenetic Control of Gene Activity
SECTION III: Epigenetic Technology
8. Analysis of Gene-specific DNA Methylation
9. Methods for Assessing Genome-wide DNA Methylation
10. Methylation of Lysine-9 of Histone H3: Role in Heterochromatin Modulation and Tumorigenesis
11. Chromatin Modifications Distinguish Genomic Features and Physical Organization of the Nucleus
12. Assessing Epigenetic Information
SECTION IV: Model Organisms of Epigenetics
13. Epigenetics of Eukaryotic Microbes
14. Drosophila Epigenetics
15. Mouse Models of Epigenetic Inheritance
16. Epigenetic Regulatory Mechanisms in Plants
SECTION V: Metabolism and Epigenetics 17. Metabolic Regulation of DNA Methylation in Mammals
18. Dietary and Metabolic Compounds Affecting Chromatin Dynamics/Remodeling
SECTION VI: Functions of Epigenetics
19. Epigenetics, Stem Cells and Cellular Differentiation
20. Epigenetic Basis of Skeletal Muscle Regeneration
21. Epigenetics of X Chromosome Inactivation
22. Genomic Imprinting
23. Epigenetics of Memory Processes
24. Transgenerational Epigenetics
25. Aging Epigenetics
SECTION VII: Evolutionary Epigenetics 26. Epigenetics in Adaptive Evolution and Development
SECTION VIII: Epigenetic Epidemiology
27. The Effects of Diet on Epigenetic Processes
28. Environmental Agents and Epigenetics
29. Impact of Microbial Infections on the Human Epigenome and Carcinogenesis
30. DNA Methylation Profiles in the 5’-Upstream Region of the Human FMR1 Promoter and in an Adenovirus Transgenome
31. Population Pharmacoepigenomics
SECTION IX: Epigenetics and Human Disease
32. Cancer Epigenetics
33. The Role of Epigenetics in Immune Disorders
34. Epigenetics of Brain Disorders
35. Complex Metabolic Syndromes and Epigenetics
36. Imprinting Disorders in Humans
SECTION X: Epigenetic Therapy
37. Clinical Applications of Histone Deacetylase Inhibitors