Preface
In our time, the sheer volume of published experimental measurements, their scope and technical sophistication, compounded with a proliferation of diverse approaches, objectives, and model systems, has made it particularly difficult to see the conceptual forest for the trees. Yet all of the elegant and sophisticated though disparate and unconnected data sets with which we are confronted represent biological output of the same fundamental operating principles. Each experimental system provides a different window which offers a pathway to these principles. In this book we provide a conceptual framework that we hope will make accessible the principles by which the genomic control system operates developmental and evolutionary process. This framework grows from the realization that the most fundamental causal principles in biology, which distinguish biology from all other sciences, emerge from the existence and function of genomic information. From the genomic sequence are to be recovered the determinants of body plan development in animals. Of course, the processes of biology are subject to the same laws of physics and chemistry as are those of the inanimate world, but it is the genome that mandates biological organization. This is not a metaphor, it is a description of mechanisms that we can now begin to perceive as an unbroken chain of causal connections, leading from the A’s, C’s, G’s and T’s of the genomic DNA to the developmental formulation of the elements of the organism.
The new field that is coalescing around the concepts of genomic information processing partakes of principles and evidence from systems biology, developmental molecular biology, various aspects of body plan evolution and phylogenetics, as well as biological engineering and computational modeling. We found it useful to select and incorporate insights from all of these fields, where these illuminate the genomic control of development, without operating wholly within the paradigms of any one of them. In this book we focus on the main characteristics of the genomic control system, which include its hierarchy, its logic processing functions and its structural organization in the form of gene regulatory networks. Such networks encompass at a system level the recognition interactions between transcription factors and DNA sequence that lie at the heart of the whole regulatory process. The general operational properties of genomic regulatory systems are shared across the Bilateria, while diversity in animal forms directly reflects diversity in genomic developmental programs. Focus on the genomic programs controlling development provides a single conceptual lens through which the most disparate phenomena of development and evolution can be viewed, causally understood and interpreted.
A brief précis of the trajectory of our treatment follows:
Chapter 1 is about the molecular biology of sequence-dependent regulation of gene expression in animal development. Here we consider three major levels at which gene expression is controlled, with respect to their roles in the developmental process. The first is transcriptional regulation by sequence-specific transcription factors and their interaction with
cis-regulatory modules. Secondly, miRNAs modulate transcript prevalence, and a third level operates by means of chromatin modifications installed upon transcription factor-DNA interactions. While the expression of many genes is affected successively by all these mechanisms, control of developmental complexity is executed by transcription factors and their sequence-specific interactions with the regulatory genome. We further conclude that the primary key to the informational process of development lies in the control system regulating the expression of genes encoding transcription factors.
Chapter 2 focusses on the transcriptional control apparatus that operates animal development. Gene regulatory network (GRN) theory defines the principal structural and functional properties of genomic control programs in animals. Here we provide an introductory overview, specifying the components of GRNs, and focusing on higher level design features such as hierarchy, modular organization, and the unidirectionality of these encoded regulatory systems. Two major aspects of GRN output are their generation of regulatory states that in turn determine all downstream genetic functions, and the Boolean nature of spatial gene expression. The genomic regulatory transactions linked together in GRNs are executed by
cis-regulatory modules, and their combinatorial information processing functions deeply affect GRN organization. This Chapter further includes a first principles quantitative treatment of network dynamics, which rationalizes the measurable kinetics of accumulation of transcriptional products and permits computational assessment of the outputs of regulatory gene cascades. Current GRN theory devolves from multiple earlier roots which we very briefly trace.
Chapter 3 focusses on the means by which the transcriptional regulatory system is deployed in the pre-gastrular development of many kinds of bilaterian animal. The fundamental task in early embryogenesis is to install in the descendants of a single cell initial patterns of spatial regulatory gene expression in respect to the axes of the future body plan. This poses control challenges unlike any others encountered in bilaterian life. We introduce in this Chapter general principles of development couched in terms of regulatory logic, such as the regulatory properties of the egg, inductive signaling, differentiation and cellular morphogenesis. Beyond these, bilaterian evolution has given rise to several distinct developmental strategies for pre-gastrular embryogenesis, specifically those of regularly cleaving small embryos with early onset of transcription; of large embryos undergoing rapid cell division with delayed onset of transcription and cell motility; of embryos utilizing a transcriptionally active syncytium. Here, for each of these strategies, we focus on particular regulatory design features of GRNs encoding embryonic specification, response to maternal spatial inputs, territorial pattern formation, and global control of zygotic gene expression.
Chapter 4 is about animal body part development. Bilaterian body parts are formed during development according to a common scheme. The basic principles, irrespective of body part or organism, emerge from studies that reveal the genomically encoded mechanisms underlying body part formation. Here we consider partial gene regulatory networks that have been solved for a diverse variety of body parts including brains, hearts, limbs, and guts, in
Drosophila and/or vertebrates. In all of these cases, the process of body part formation begins with the allocation of a progenitor field, defined by installation of an initial regulatory state, and its placement in respect to the axes of the body plan. There follows the progressively finer subdivision of this field into appropriately positioned regulatory state domains that generate the subparts and ultimately the cell types of the body part. Circuitry commonly encountered in these GRNs controls signaling interactions, exclusion functions and boundary formation, and often involves feedback and feed forward regulation.
Chapter 5 considers the differentiation of cell types as the final readout of the preceding spatial specification processes in development of the body plan. Cell types represent the installation of biological and molecular effector functions within the matrix of spatial regulatory states. Here the focus is on the specific genomically encoded wiring utilized for deployment of cohorts of effector genes in terminal differentiation. Two objectives require to be fulfilled: one is the regional activation and permanent maintenance of expression of a small set of driver regulatory genes; and the other is control of large sets of effector genes by these drivers. The first is accomplished by positive feedback circuitry among the driver genes, usually accompanied by exclusion of drivers of alternative cell fates, and the second depends on effector gene
cis-regulatory architecture. Our examples include
Drosophila photoreceptors, and differentiation of erythrocytes, somitic muscle, neural crest and placodes in vertebrates. Diverse body parts often deploy similar cell types and this is mediated by modularity of genomic regulatory systems.
In
Chapter 6 we analyze diverse approaches to construction of quantitative and logic models of gene regulatory networks. The structural and functional properties of GRNs can be accessed only by use of models. In this Chapter we consider diverse forms of GRN model, focusing on insights into the biology of developmental GRNs that accrue from the generation of abstract mathematical, logical or topological models. Topological models provide genome-centered maps of regulatory linkages, and thus graphically represent the architecture of causal interaction networks. We address the significance of network topology in an extensive comparative structure/function analysis of GRN subcircuit architecture. Insights otherwise unattainable emerge from dynamical mathematical treatment of GRN function. We review informative applications of ODE analysis to developmental GRNs operating in
Drosophila embryos and in mammalian hematopoietic cells, and consider the regulatory interpretation of morphogen gradients. We turn then to Boolean models which are focused on GRN logic transactions. Several asynchronous models are considered and we end with a summary of the new insights deriving from a comprehensive Boolean logic model of the sea urchin embryo...
