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Polyploidy, increased copy number of whole chromosome sets in the genome, is a common cellular state in evolution, development and disease. Polyploidy enlarges cell size and alters gene expression, producing novel phenotypes and functions. Although many polyploid cell types have been discovered, it is not clear how polyploidy changes physiology. Specifically, whether the enlarged cell size of polyploids causes differential gene regulation has not been investigated. In this thesis, I present the evidence for a size-sensing mechanism that alters gene expression in yeast. My results indicate a causal relationship between cell size and gene expression. Ploidy-associated changes in the transcriptome therefore reflect transcriptional adjustment to a larger cell size. The causal and regulatory connection between cell size and transcription suggests that the physical features of a cell (such as size and shape) are a systematic factor in gene regulation. In addition, cell size homeostasis may have a critical function - maintenance of transcriptional homeostasis.
Volume is a fundamental morphological feature of cells, influencing a wide variety of cellular processes. Because it is coupled to so many processes, cells employ regulatory mechanisms to ensure cells exhibit a limited range of sizes. Recent work in budding yeast has shown that a key cell cycle regulator, the G1/S transcriptional inhibitor Whi5, is synthesized independent of cell size. The dilution of Whi5 in larger cells links cell size to G1/S cell cycle progression. However, it has also been shown that growth over the full cell cycle does not depend on cell size at birth, termed an "adder". It has been proposed that this observation suggests that cell size is controlled over the course of the full cell cycle, leading to an apparent contradiction. Here we show that cell size control occurs independently in different parts of the cell cycle and does not reflect a molecular mechanism measuring growth during the full cell cycle. Consistent with previous results, we find that cell size sets the rate of entry into the cell cycle during the pre-Start period. We also identify the key parameters predicting the rate of entry into cytokinesis at the end of the post-Start period. We use these parameters to build a phenomenological cell cycle model that recapitulates observations of growth and size distributions for cells without explicit coupling between cell cycle phases. Our model predicts that changes to the rate of progression through either phase of the cell cycle should disrupt the adder behavior and we show that mutants in genes controlling G1/S size control breaks the adder. The rate of passage through Start depends on volume, which is thought to depend on the size-independent expression of Whi5. This type of gene expression scaling is unusual because although cells of a given type may span a range of sizes, most proteins and RNA are maintained at constant, size independent, concentrations, rather than amounts. This ensures that biochemical reactions proceed independently of cell size. The identification of WHI5, whose gene product differs from this pattern, raises two fundamental questions: (1) Are there additional genes whose synthesis is decoupled from cell volume? (2) If most gene expression is proportional to cell size, what molecular mechanism promotes cell-size-independent gene expression? To address these questions, we analyzed flow cytometry data collected using the yeast GFP-fusion library. We identified approximately 200 genes whose expression is not proportional to cell volume. Gene ontology analysis revealed that non-scaling genes are enriched for genes with roles in DNA-templated processes and membrane transport. This suggests that cells employ differential protein synthesis to coordinate protein requirements with the scaling properties of cellular structures. Membranes are expected to scale as size2/3 and DNA content is independent of size. To understand the mechanisms that underlie size-independent gene expression, we used transcriptional reporters of non-scaling genes, including WHI5, and determined that cell-size-independent regulation of some genes is due to non-scaling transcription rates. Targeted analysis of the WHI5 promoter showed that the region between 1000 bases and 550 bases upstream of the translation start site are required for cell-size-independent gene expression. This suggests there is a molecular element within this region required for non-scaling gene expression. Finally, we identify a partitioning mechanism ensuring proteins are partitioned in dividing cells in amounts that are independent of asymmetric sizes of the mother and daughter cells. Tight chromatin association ensures that proteins are segregated in equal amounts despite asymmetric division. Consistent with this model, while Whi5 is normally partitioned in equal amounts, a Whi5 protein that lacks the domain required for association with transcription factors is partitioned in proportion to the mother-daughter cell size ratio. Taken together, our work demonstrates a functional role for differential size-dependency of protein synthesis and gives insights into the underlying molecular mechanism(s).
Recent breakthroughs in the field of cell growth, particularly in the control of cell size, are reviewed by experts in the three major divisions of the field: growth of individual cells, growth of organs, and regulation of cell growth in the contexts of development and cell division. This book is an introductory overview of the field and should be adaptable as a textbook.
This book is the first volume in a new series Progress in Gene Expres sion. The control of gene expression is a central-most topic in molecular biology as it deals with the utilization and regulation of gene informa tion. As we see huge efforts mounting all over the developed world to understand the structure and organization of several complex eukaryotic genomes in the form of Gene Projects and Genome Centers, we have to remember that without understanding the basic mechanisms that gov ern the use of genetic information, much of this effort will not be very productive. Fortunately, however, research during the past seven years on the mechanisms that control gene expression in eukaryotes has been extremely successful in generating a wealth of information on the basic strategies of transcriptional control. (Although regulation of gene ex pression is exerted at many different levels, much of the emphasis in this series will be on transcriptional control. A future volume, however, will deal with other levels of regulation). The progress in understanding the control of eukaryotic transcription can only be appreciated by realizing that seven years ago we did not know the primary structure of a single sequence specific transcriptional activator, and those whose primary structures were available (e. g. , homeo domain proteins) were not yet recognized to function in this capacity.
The use of molecular biology and biochemistry to study the regulation of gene expression has become a major feature of research in the biological sciences. Many excellent books and reviews exist that examine the experimental methodology employed in specific areas of molecular biology and regulation of gene expression. However, we have noticed a lack of books, especially textbooks, that provide an overview of the rationale and general experimental approaches used to examine chemically or disease-mediated alterations in gene expression in mammalian systems. For example, it has been difficult to find appropriate texts that examine specific experimental goals, such as proving that an increased level of mRNA for a given gene is attributable to an increase in transcription rates. Regulation of Gene Expression: Molecular Mechanisms is intended to serve as either a textbook for graduate students or as a basic reference for laboratory personnel. Indeed, we are using this book to teach a graduate-level class at The Pennsylvania State University. For more details about this class, please visit http://moltox. cas. psu. edu and select “Courses. ” The goal for our work is to provide an overview of the various methods and approaches to characterize possible mechanisms of gene regulation. Further, we have attempted to provide a framework for students to develop an understanding of how to determine the various mechanisms that lead to altered activity of a specific protein within a cell.
The cause of cancer and its many manifestations is at present unknown. Since many of its manifestations, including is control of cell division, appear to represent abnormal patterns of gene expression, studies of the regulation of gene expression nwill provide important insights in the understanding and treatment of cancer. This volume attempts to present some of the recent work on regulation of gene expression in eukaryotic cells.
Over the past few years there have been considerable advances in our understanding of cellular control mechanisms, and current research is now linking areas of biology that were previously thought of as being quite separate. Molecular Aspects of Cellular Regulation is a series of occasional books on multidisciplinary topics which illustrate general principles of cellular regulation. Previous volumes described Recently Discovered Systems of Enzyme Regulation by Reversible Phosphorylation (Volumes 1 and 3), The Molecular Actions of Toxins and Viruses (Volume 2), Molecular Mechanisms of Transmembrane Signalling (Volume 4) and Calmodulin (Volume 5). This sixth volume, The Hormonal Control of Gene Transcription, has now been published to highlight recent important advances in our understanding of this topic which is linking two of the most active areas of current biochemical and molecular biological research (hormone action and gene transcription) and leading to the emergence of unifying concepts.
The cause of cancer and its many manifestations is at present unknown. Since many of its manifestations, including is control of cell division, appear to represent abnormal patterns of gene expression, studies of the regulation of gene expression nwill provide important insights in the understanding and treatment of cancer. This volume attempts to present some of the recent work on regulation of gene expression in eukaryotic cells.
This book, which results from the dramatic increase in interest in the control mechanism employed in gene expression and the importance of the regulated proteins, presents new information not covered in Translational Regulation of Gene Expression, which was published in 1987. It is not a revision of the earlier book but, rather, an extension of that volume witl, special emphasis on mecha nIsm. As the reader will discover, there is enormous diversity in the systems employing genes for translational regulation in order to regulate the appearance of the final product-the protein. Thus, we find that important proteins such as protooncogenes, growth factors, stress proteins, cytokines, lymphokines, iron storage and iron-uptake proteins, and a panorama of prokaryotic proteins, as well as eukaryotic viral proteins, are translationally regulated. Since for some gene products the degree of control is greater by a few orders of magnitude than their transcription, we can state that for these genes, at least, the expression is translationall y controlled. Translational regulation of gene expression in eukaryotes has emerged in the last few years as a major research field. The present book describes mechanisms of translational regulation in bacteria, yeast, and eukaryotic viruses, as well as in eukaryotic genes. In this book we try to provide in-depth coverage by including important examples from each group rather than systematically including all additional systems not described in the previous volume.