Taking Epigenetics Center Stage

These days, one hears a lot about epigenetics and epigenetic regulation. Attesting to the current popularity of the subject, a PubMed search using “epigenetics” as the key word returns 17,233 entries (from 1964 to 2006), of which 86% date from the year 2000. What exactly is epigenetics and why has there been this recent surge of interest in this subject? For those researchers working on epigenetics-related problems and those about to do so, we are fortunate that a new book entitled Epigenetics, which provides answers to these questions and more, is now available. This book, the first to be dedicated solely to the subject of epigenetics, has been brought to us thanks to the valiant efforts and foresight of its three editors—C. David Allis, Thomas Jenuwein, and Danny Reinberg—and their associate editor Marie-Laure Caparros. The editors enlisted a group of over forty prominent epigenetics researchers, who each bring their expertise and insights to the 24 chapters of this book that cover the history as well as the current state of epigenetics research.Epigenetics begins with two chapters on the history of epigenetics followed by a chapter written by the three editors that provides basic concepts and an overview of the epigenetics field. The subsequent chapters (4–9) are devoted to epigenetic studies in various model organisms. It was in such model organisms that epigenetic phenomena (such as non-Mendelian inheritance) were first observed. The book also includes discussion of the molecular mechanisms involved in epigenetic regulation (chapters 10–14), investigation of the classical epigenetic phenomenon of X-inactivation in various model organisms (chapters 15–17), and discussion of DNA methylation, imprinting, stem cell pluripotency, nuclear reprogramming, and lymphopoiesis (chapters 18–22). The book ends with two chapters (23, 24) that highlight the potential link between epigenetic regulation and complex human diseases including cancer and pinpoint the emerging key role of epigenetics in development and disease. The historical accounts of the rise of epigenetics as a field of study, combined with the inclusion of cutting-edging epigenetics research in various biological processes and model organisms, provide the reader with a clear sense of what epigenetics research is about, where it came from, where it is now, and where it is headed. It will prove to be the book that everyone with an interest in epigenetics would want to have and read.View Large Image | View Hi-Res Image | Download PowerPoint SlideAccording to the American Heritage dictionary, “epi” is the Latin prefix meaning above, over, outside, or beside. Thus, epigenetics literally refers to events that are above and beside genetics, that is, beyond DNA sequence alterations. As Gary Felsenfeld notes in chapter 2 (page 16), the meaning of the word epigenetics has evolved from its first use more than 50 years ago by Waddington, who referred to phenotypic changes that occur from cell to cell during development as the “epigenetic landscape.” Over the years, it became necessary to redefine epigenetics as more and more examples of heritable changes that do not appear to involve genetic alterations were discovered in different organisms. In the first chapter (page 2), Dan Gottschling provides a succinct working definition of epigenetics, referring to epigenetic phenomena as “a change in phenotype that is heritable but does not involve DNA mutation.” He further notes that the change in phenotype must be switch-like and heritable (that is, it must persist through subsequent cell divisions and be propagated through the germline) even when the initial conditions that caused the switch disappear (an important feature of epigenetic phenomena). In their overview (chapter 3, page 29), Allis, Jenuwein, and Reinberg crystallize a molecular definition of epigenetics as “the sum of the alterations to the chromatin template that collectively establish and propagate different patterns of gene expression (transcription) and silencing from the same genome.”The components of the chromatin template—DNA and histone proteins—are the main substrates that are subject to alterations leading to distinct chromatin states. These changes are bought about by DNA methylation (chapter 18), variant histones (chapter 13), and both noncovalent and covalent modifications of chromatin by ATP-dependent chromatin-remodeling protein complexes and numerous enzymatic machineries (chapters 3 and 10). Histone modifications include acetylation, methylation, phosphorylation, ubiquitination, sumoylation, ADP ribosylation, and proline isomerization, among others. Whereas the role of DNA methylation in epigenetic regulation is well established, it remains to be seen whether all types of histone modifications contribute to the epigenetic state or whether only some modifications are epigenetic in nature. However, interpretation and integration of the “meaning” of various histone modifications is likely to be carried out by proteins that recognize and bind to modified histones. A prime example is the evolutionarily conserved protein HP1, which specifically recognizes methylated lysine 9 on histone H3 (H3K9me) via its chromodomain and helps to propagate a H3K9me signal, which is critical for gene silencing (chapters 3 and 10). In addition to chromodomains, plant homeodomains (PHD) and Tudor domains also recognize methylated lysines; bromodomains, on the other hand, appear to recognize acetylated lysines. The importance of these histone-binding proteins in epigenetic regulation is reiterated throughout the book, and no doubt these proteins will soon warrant a chapter all to themselves.Like many scientific disciplines, the study of epigenetics began with a collection of unexpected and unusual phenomena in both familiar and exotic organisms. These include position-effect variegation in the fruit fly Drosophila, paramutation in maize, silent mating type in the budding yeast Saccharomyces cerevisiae, X-chromosome inactivation in female mammals, imprinting, and more recently RNA interference in heterochromatin formation in the fission yeast S. pombe and plants, as well as the propagation of prion proteins. Although unclear at the time of the discoveries, these phenomena ultimately proved to be related and to share a common feature, that is, the heritable changes brought about by these events were all epigenetic in nature and did not require alterations to DNA sequences. Collectively, these discoveries highlight the importance of paying attention to unusual phenomena in scientific discoveries and how seemingly disparate events are in fact related in fundamental ways. They also reinforce the critical importance of model organisms. Wisely, the book devotes ample space to discussion of epigenetic investigations in model organisms ranging from the budding yeast S. cerevisiae (chapter 4) to Drosophila (chapter 5), the fungus Neurospora crassa (chapter 6), ciliates (chapter 7), S. pombe and plants (chapters 8 and 9), the nematode Caenorhabditis elegans (chapter 15), and mammals (chapters 17–19). The book also brings to readers emerging and pressing issues of current biology where epigenetics may play a pivotal role. These include the control of stem cell pluripotency (chapter 20), nuclear transplantation and reprogramming of the genome (chapter 22), as well as human diseases (chapters 23 and 24).All in all, this is a well-balanced book that covers the fundamentals of epigenetics as well as its emerging roles in many different areas where medically relevant interests lie. It is worth noting that in addition to the excellent coverage of many different facets of epigenetics and underlying molecular mechanisms, the book includes useful weblinks. In addition, a plethora of tables listing myriad histone modifications and their roles in chromatin and transcriptional regulation are sure to benefit the uninitiated as well as veterans of the epigenetics field.Epigenetics as a field of study had a humble beginning, originating with a collection of observations that depict patterns of inheritance that could not be explained by simple genetics and Mendel's law of heredity. The field now has matured and is expected to have far-reaching effects on many areas of biological research. This book is the best testament to a research field that has finally come of age. Epigenetics research not only holds tremendous promise for revealing the inner workings of complex biological systems but also yields the hope that new therapeutic targets and strategies may be found among the many regulators of chromatin. It will take not only this generation of epigenetics researchers but also future generations to realize and fulfill these promises, in particular the therapeutic potential of epigenetics. This timely and comprehensive book will undoubtedly serve as an important catalyst for driving epigenetics research forward to benefit us all.