The Regulatory Genome, by Eric H. Davidson (2006),. Academic Press. Igor B.
Dawid1. Laboratory of Molecular Genetics, National Institute of Child Health and.
The FASEB Journal • Book Review
The Regulatory Genome, by Eric H. Davidson (2006), Academic Press
Igor B. Dawid1 Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA More than one hundred years ago the notion emerged that the genome, as we would now call it, is constant among the various differentiated cells in the body. How, then, can the same heritable instructions generate the multiple cell types, organs and body shapes of different animals? The answer was differential gene expression, but it raised new questions— how are genes turned on and off, and how is gene activity coordinated during differentiation and pattern formation in time and space? Explanations began to emerge with the rise of molecular biology, rapidly progressing from gene isolation through measuring and visualizing gene expression to the study of cis-regulatory sequences and their binding to an ever-increasing variety of transcription factors. Regulatory systems proved highly complex—not only do various transcription factors regulate many genes, but each gene receives input from many factors, and importantly, many of these interactions involve the regulation of transcription factor genes themselves. Clearly, we would never understand gene regulation or embryonic development by looking at one gene at a time! Enter the concept of regulatory networks, the subject of this book. Eric Davidson has studied and written about molecular mechanisms of animal development almost since the beginning of this subject. His first book (1968) went through several editions and was a major resource for information on what types of RNA are produced at what time in the embryo. A new book appeared in 2001, reflecting progress in the study of transcriptional regulation during the preceding two decades. The author tells us that he was moved to write the present monograph when he considered a second edition of the previous volume, only to find the landscape so much changed that a new work was called for. The result is
1
Correspondence: Laboratory of Molecular Genetics, NICHD, NIH, Building 6B, Rm. 4B413, 6 Center Dr., Bethesda, MD 20847, USA. E-mail:
[email protected] doi: 10.1096/fj.06-1103ufm 2190
The Regulatory Genome whose subtitle, Gene Regulatory Networks in Development and Evolution, describes the work even better. In this book, the author presents overall principles of gene regulation through cis-regulatory sequences, the concept of gene regulatory networks, a view of animal development as a manifestation of network function, and a discussion of bilaterian evolution from the perspective of network conservation and modification. The book is laid out in five chapters, beginning with an introduction of general concepts. Properties of cis-regulatory elements are summarized in lucid terms, for example, in a figure that shows the regulation of multiple genes encoding contractile proteins by combinations of a limited number of transcription factor sites in never-repeated variations. In setting the framework for the entire book, the author quickly proceeds to some strongly profiled statements. Regulatory genes are defined as encoding sequence-specific transcription factors, while modification of chromatin structure, alternative splicing, translational control, and regulatory RNAs are said to affect later development or downstream events. Chapter two elaborates on the functions of cisregulatory regions in development. What emerges, beyond the complexity of these regions, is their modular structure in which various sub-regions are responsible for specific biological actions. The examples come from various animals, but here and elsewhere, the prime models are the sea urchin and Drosophila. A star example is the sea urchin endo16 gene, as studied in great detail in the author’s laboratory, whose complex regulation is probably typical of other genes because, as stated with an admirable lack of paternal pride, endo16 is just “a garden variety gene” expressed in differentiating cells. The next chapter looks at it all from the point of view of the embryo. Issues of localization of maternal information in the egg, initial differentiation of the early embryo, and progenitor fields in subsequent development are discussed from the point of view of transcriptional regulation. Bilaterian embryos 0892-6638/06/0020-2190 © FASEB
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are divided into two categories, type 1 (small, simple, and largely lineage dependent) and type 2 (large, complex, and more regulative), although it is not clear that this organization advances the network analysis to come. These two chapters link the book to its predecessor and build a foundation for the subsequent presentation. The chapter on “Gene Regulatory Networks for Development” is the centerpiece of this book. It summarizes a field, largely created by the author and his collaborators, which has formalized the description of information on gene regulation with the aim to describe the entire regulatory machinery responsible for a developmental process. This machinery is described in terms of properties of cis-regulatory module inputs and outputs so that “. . .this information suffices to explain why the regulatory and signaling genes in the internal domain of the network are differentially expressed at successive stages. Therefore they explain how the developmental process is controlled.” A lofty goal indeed, and one that succeeds to a considerable extent. In my mind, the strength of this approach is the application of a formalized notation to gene interactions, which makes it practical to deal with complex systems. Some readers might be discouraged by the thought that “it is too complicated.” The answer is, I should think, “this is life.” It is complicated. The network approach doesn’t make it so, it may just appear this way because it undertakes to consider, ideally, all relevant genes in a process rather than a select subset, as most conventional publications and discussions do. This said, there are also some reservations. This approach considers signaling as just a more circuitous path from one cis-regulatory element to another and, as we saw above, relegates chromatin structure, translational control, etc., to a status of minor significance. Perhaps this is
one reason why, among the three major examples listed, sea urchin endomesoderm and Drosophila dorsal/ventral specification succeed much better than Xenopus mesoderm specification. Finally, bilaterian evolution is viewed from a gene network perspective. This chapter is the most fun. It is full of interesting points, giving each reader both new insights and some issues with which to disagree. Claims for homology in eye evolution are vigorously challenged on the basis that just similar genes are not enough to prove homology. Only fully conserved network modules, where regulatory interactions between orthologous genes are conserved, would seem to be acceptable. Such a conserved module is presented for endoderm specification in sea urchins and starfish, which have been separated for some 500 million years. This time is impressive, yet these are members of the same phylum, whereas all bilaterians are considered in the discussion of eye evolution; it seems to be a bit of a double standard. The question appears to me, what kind of molecular evidence can validly be adduced to conclude that a developmental process is derived from a common ancestor? If a perfectly conserved network module is required, chances are that we may loose valuable indications contained in less perfect data. Indeed the subsequent discussion in this chapter proceeds to less perfect data in searching for possible homology, albeit with clear warnings attached to the limitations of the data. Readers will no doubt find this chapter stimulating and thought provoking. Altogether this is a highly informative book, provocative in the best sense of the word, and very much at the forefront of the field of developmental biology in the “post-genomic” era. I recommend it highly to anyone interested in the subject.
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The Regulatory Genome, by Eric H. Davidson (2006), Academic Press Igor B. Dawid FASEB J 2006 20: 2190-2191 Access the most recent version at doi:10.1096/fj.06-1103ufm
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