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Genes & Signals


Subject Area(s):  Developmental BiologyCell BiologyMolecular BiologyGeneticsBiochemistryCancer Biology

By Mark Ptashne, Memorial Sloan-Kettering Cancer Center; Alexander Gann, Cold Spring Harbor Laboratory

Online Features: Website


© 2002 • 192 pp., illus., index
Kindle •
ISBN  978-087969633-7

Available only on the Amazon Kindle

Visit the Genes & Signals web site.

This site is a companion to the book and provides free access to downloadable versions of all the figures found in the book and references to work discussed in the footnotes. We hope you'll take the time to browse the site and send us your feedback.

Click on the link below to view a series of lectures based on the book delivered by Mark Ptashne at Rockefeller University in January of 2002.

Lectures by Mark Ptashne at Rockefeller University.
This link will open in a new browser window.


  •     Description    
  •     Contents    
  •     Reviews    
  •     Related Titles    

Description

Genes & Signals analyzes gene regulation from a new perspective. The first chapter describes mechanisms found in bacteria, and two subsequent chapters discuss which of these is most highly exploited in higher organisms. A final chapter relates these molecular strategies to other enzymatic processes, including those involving kinases, RNA splicing enzymes, proteases, and others. A general theme emerges, one that proposes how a rather restricted set of signals and enzymatic functions has been used in evolution to generate complex life forms of different types.

Contents

Introduction
The importance of gene regulation in two biological contexts is described. First, during development of a complex organism, genes are switched on and off in elaborate patterns; and second, changes in those patterns of gene regulation drive many evolutionary changes in organisms. The problem is to understand what kinds of molecular interactions, and what kinds of changes in those interactions, drive these processes. The history of certain key ideas, as developed primarily by Jacob, Monod and Lwoff in Paris some 40 years ago is briefly reviewed. A new perspective on the problem is suggested: gene regulation is construed as a process of imposing specificity on an enzyme, RNA polymerase. The most revealing analysis will be of the phenomenon called "gene activation."
Chapter 1: Lessons from Bacteria
Three mechanisms for activating transcription of specific genes in E.coli are presented. The simplest – and most common – is called "Regulated Recruitment". In this case, the activator – a DNA binding protein that switches on expression of a gene – only has to recruit an enzyme – RNA polymerase – to the gene. Examples of this mechanism (as found at the lac genes and genes of phage lambda) are described in detail, along with the experimental approaches used to elucidate the mechanism. The other two mechanisms – in which either the polymerase or the gene must undergo a structural change induced by an activator – are again illustrated using examples of each (control of the glnA gene by NtrC; and control of the merT gene by MerR); again, the experimental basis for the proposed mechanisms is in each case described.
Where they are used, the roles of repressors – DNA binding proteins that switch off the expression of specific genes – are discussed. How extra-cellular signals control the activities of activators and repressors is examined. Also, the ways in which two activators, or an activator and a repressor, can work together to integrate signals at a given gene is discussed. Often the same regulators can be used in different combinations – a phenomenon called "combinatorial control".
The rather simple "adhesive" protein surfaces required for regulated recruitment are emphasized. Other aspects, such as the phenomenon of cooperativity, are discussed in some detail.
Chapter 2: Yeast: A Single-celled Eukaryote
Which of the three basic mechanisms of gene activation found in bacteria is used to switch on the typical yeast gene? This is the question asked in this chapter.
As in bacteria, genes in yeast can be switched on by activators and switched off by repressors. As in bacteria, these regulatory proteins are controlled by extra-cellular signals. But unlike the bacteria cases – where the "transcription machinery" consisted of a single enzyme (RNA polymerase) – in eukaryotes, even the relatively simple yeast, that machinery is far more complicated. And in addition, the genes themselves are wrapped in histones to form nucleosomes.
Despite these complications, many of the same experiments that were revealing in bacteria can be performed in yeast as well. (Control of the GAL1 gene by the activator Gal4 is taken as an example). These experiments reveal that, despite the complexities, regulated recruitment is the basic mechanism of activation in yeast. In this case, enzymes that modify the state of nucleosomes in various ways, or that promote transcriptional elongation as well as initiation, are often recruited, along with the basic transcriptional machinery, to switch on genes. Thus a general theme emerges: simple molecular interactions can be reiterated and supplemented by "add ons", as evolution proceeds, to create ever more sophisticated regulatory responses.
The role of repressors (e.g. Mig1/TUP1 repression of GAL1) is discussed as well, as are examples of signal integration and combinatorial control (in regulation of the yeast mating type genes; and of the HO gene), and the phenomenon of "gene silencing".
Chapter 3: Some Notes on Higher Eukaryotes
Evidently regulated recruitment explains the action of the typical activator from higher eukaryotes – mammals, flies etc – just as it does that from yeast. The evidence is discussed at the beginning of this brief chapter.
But higher eukaryotes use signal integration and combinatorial control to a far greater extent than either yeast or bacteria. This allows them to produce an extraordinary range of patterns of gene expression – something which in turn allows these organisms to be so complex and varied despite the relatively "small" number (and similar types) of genes they each posses. How the activators and repressors achieve this is discussed (using the human interferon-beta gene, and the Drosophila eve gene as examples). Finally, one or two other characteristic problems faced by higher eukaryotes – e.g. activation at a distance, imprinting etc – are also described and the extent to which they can be explained in terms of regulated recruitment discussed.
Chapter 4: Enzyme Specificity and Regulation
In this final chapter, the principles of regulation uncovered in our survey of transcription are applied to enzymes involved in other processes – signal transduction, protein degradation, the cell cycle, splicing etc. Regulated Recruitment is found to play a large part in how specificity and regulation are imposed on many of these enzymes – e.g. kinases, phosphatases, and ubiquitylating enzymes. The dangers and benefits of regulating enzymes in this way are considered, as are the problems of interpreting certain commonly performed experiments involving enzymes that work in this way.
Afterword
The book ends with some thoughts on how ideas in these areas have developed over time.

Reviews

review:  "This book opens up the basic molecular language that cells use for their internal organization and to communicate with the outside world. This is important, and fascinating, for anyone interested in how cells work and how regulatory systems evolve."
      —From the Foreword by Tony Pawson

review:  "I read this book with great pleasure. I have always been convinced that the same principles operating in bacteria are also operating in higher organisms with added complexity. The question therefore is to understand what kind of complexity is involved and how it is geared. This is a necessary book (which is a rare thing!)."
      —François Jacob

review:  "It's a great synthesis making the field accessible to a wide scientific audience and putting forward provocative and stimulating ideas. Scientists interested in interpretting genomes will find it an invaluable guide to thinking about the regulatory information encoded in the chromosomes."
      —Eric Lander

review:  "There is nothing out there that gives such a broad, deep and up to date view of transcription regulation and the general problem of specificity. My students think the book is great–important ideas and concepts are clearly described and beautifully illustrated."
      —Tom Maniatis, Harvard University

review:  "Genes & Signals reduces the immense and sometimes bewildering literature on the control of gene expression to simple principles. Amazingly, it manages to do so by providing a framework for the experimental evidence rather than concealing it. It is a beautiful presentation, which can be appreciated by readers at all levels."
      —Frank Stahl

review:  "A compelling and deeply conceptual work about how biological reactions are regulated. . . . What this book provides is a guide to the concepts that form the framework for the gene expression field. The concepts allow students to understand the context of the facts and apply this information to their own studies. Students who are lucky enough to read Genes & Signals won't be slithering out of transcription seminars in 30 years, when our field has been condensed to an in silico version of an intermediary metabolism wall chart."
      —Nature Genetics

review:  "This book should win a wide readership, especially among young people intrigued—but not satisfied—by entry–level biology courses. Applying simple principles to the dazzling particularity of gene expression, Genes & Signals will give students a glimpse of the beauty and fascination of molecular biology. This book should also be required reading for professionals who (like the reviewer) learned their biology without being initiated into the mysteries of lac and l gene regulation. We 'already knew that,' perhaps. But the lesson is easy to forget as we trudge through blizzards of genomic and proteomic information. It helps to be reminded, yet again, how complexity creates itself by combining small numbers of simple mechanisms."
      —Current Biology

review:  "In Genes & Signals, Ptashne and Gann have written a unique book that is driven by ideas and broad concepts, yet is based on solid information. It is accessible to undergraduates with some knowledge of biology, yet it is also valuable to experts in the field. I highly recommend it."
      —Nature

review:  

"Ptashne and Gann have written a clear and intelligent distillation of the various assembly pathways, especially in transcription initiation.

The authors start with the simplest systems, phage and bacteria, and work toward the more complex. . . .

. . . A major strength of Genes & Signals is the spare use of experimental detail. An experimental approach is described briefly, e.g., crosslinking, and the results of the experiment and its implication for the biochemistry of the reaction under study are stressed. This approach is highly successful and the inverse of more conventional presentations, where experimental detail is laboriously elaborated and the conclusions to be drawn given short shrift. The artwork, by the way, is a pleasure. . . .

Because of the clarity and logic of the presentation, Genes & Signals can be recommended for a very wide audience, from college students to experienced researchers. It is not long, it's fun, and it makes you think."
      —Cell

review:  "The text of the book is beautifully crafted; the reader is taken on a journey from one section to the next in a seamless manner. The book makes extensive use of footnotes that are included at the end of each chapter so that those of us who want to know more can understand the basis of many of the statements made within the text itself. Furthermore, the illustrations are both beautifully drawn and immensely helpful. Ptashne and Gann have again distilled complex subjects into a readily understandable form. Its thought–provoking nature, clarity, and accessibility make it an essential read."
      —The Biochemist

review:  "I cannot over emphasize the clarity of the prose in this book. Any student remotely interested in molecular biology will be enthralled from first page to last."
      —Biochemistry and Molecular Biology Education

review:  "The authors have managed to create a book that is very useful for the novice in this field, while also proving somewhat beneficial to those who have a more detailed background but are looking for a deeper insight into one topic. The novice will be able to walk away with a good and detailed summary of many processes and principles regulating transcriptional initiation in a range of organisms."
      —Journal of Cell Science