Control Mechanisms In The Expression Of Cellular Phenotypes

Control Mechanisms in the Expression of Cellular Phenotypes documents the proceedings of a symposium of the International Society for Cell Biology. In progressively widening investigations, phenotypic expression has come to a critical focus not only in the developmental biology of animal and plant cells, but also in such fields as immunology, cytogenetics, enzymatic regulation, and tumor biology. It was for this reason that the present symposium was organized as a means of bringing together investigators of widely different backgrounds. The contributions made by researchers at the symposium include studies on gene expression in allophenic mice; the regulation of uridine 5-monophosphate synthesis in human diploid cells; the melanotic expression of embryonic pigment cells; and clonal cell lines of neurons. Other papers deal with biochemical genetics studies on mammalian cells in vitro; embryos from somatic plant cells; somatic cell hybrids as tools for genetic studies in man; and utilization of somatic cells for genetic analysis.

Many inheritable changes in gene function are not explained by changes in the DNA sequence. Such epigenetic mechanisms are known to influence gene function in most complex organisms and include effects such as transposon function, chromosome imprinting, yeast mating type switching and telomeric silencing. In recent years, epigenetic effects have become a major focus of research activity. This monograph, edited by three well-known biologists from different specialties, is the first to review and synthesize what is known about these effects across all species, particularly from a molecular perspective, and will be of interest to everyone in the fields of molecular biology and genetics.

Epigenetic Gene Expression and Regulation reviews current knowledge on the heritable molecular mechanisms that regulate gene expression, contribute to disease susceptibility, and point to potential treatment in future therapies. The book shows how these heritable mechanisms allow individual cells to establish stable and unique patterns of gene expression that can be passed through cell divisions without DNA mutations, thereby establishing how different heritable patterns of gene regulation control cell differentiation and organogenesis, resulting in a distinct human organism with a variety of differing cellular functions and tissues. The work begins with basic biology, encompasses methods, cellular and tissue organization, topical issues in epigenetic evolution and environmental epigenesis, and lastly clinical disease discovery and treatment. Each highly illustrated chapter is organized to briefly summarize current research, provide appropriate pedagogical guidance, pertinent methods, relevant model organisms, and clinical examples. Reviews current knowledge on the heritable molecular mechanisms that regulate gene expression, contribute to disease susceptibility, and point to potential treatment in future therapies Helps readers understand how epigenetic marks are targeted, and to what extent transgenerational epigenetic changes are instilled and possibly passed onto offspring Chapters are replete with clinical examples to empower the basic biology with translational significance Offers more than 100 illustrations to distill key concepts and decipher complex science

Gene expression is the most fundamental level at which genotype gives rise to phenotype, which is an obvious, observable, and measurable trait. Phenotype is dependent on genetic makeup of the organism and influenced by environmental conditions. This book explores the significance, mechanism, function, characteristic, determination, and application of gene expression and phenotypic traits.

This textbook aims to describe the fascinating area of eukaryotic gene regulation for graduate students in all areas of the biomedical sciences. Gene expression is essential in shaping the various phenotypes of cells and tissues and as such, regulation of gene expression is a fundamental aspect of nearly all processes in physiology, both in healthy and in diseased states. This pivotal role for the regulation of gene expression makes this textbook essential reading for students of all the biomedical sciences, in order to be better prepared for their specialized disciplines. A complete understanding of transcription factors and the processes that alter their activity is a major goal of modern life science research. The availability of the whole human genome sequence (and that of other eukaryotic genomes) and the consequent development of next-generation sequencing technologies have significantly changed nearly all areas of the biological sciences. For example, the genome-wide location of histone modifications and transcription factor binding sites, such as provided by the ENCODE consortium, has greatly improved our understanding of gene regulation. Therefore, the focus of this book is the description of the post-genome understanding of gene regulation. The purpose of this book is to provide, in a condensed form, an overview on the present understanding of the mechanisms of gene regulation. The authors are not aiming to compete with comprehensive treatises, but rather focus on the essentials. Therefore, the authors have favored a high figure-to-text ratio following the rule stating that “a picture tells more than thousand words”. The content of the book is based on the lecture course, which is given by Prof. Carlberg since 2001 at the University of Eastern Finland in Kuopio. The book is subdivided into 4 sections and 13 chapters. Following the Introduction there are three sections, which take a view on gene regulation from the perspective of transcription factors, chromatin and non-coding RNA, respectively. Besides its value as a textbook, Mechanisms of Gene Regulation will be a useful reference for individuals working in biomedical laboratories.

Molecular and Cellular Approaches to the Control of Proliferation and Differentiation focuses on molecular and cellular approaches used to control cell proliferation and differentiation. This book discusses the basic mechanisms involved in the regulation of cell growth, emphasizing the coupling of proliferation and the progressive expression of several specific cellular phenotypes. This text is organized into three sections encompassing 12 chapters and begins with an introduction to cell proliferation and how it is regulated by growth factors and nuclear protooncogenes in cell proliferation. The book then discusses mitosis and its investigation by means of the cell biological, genetic, biochemical, and immunological approaches, along with the model for mitotic regulation. The next chapters examine the manner in which cell structure is involved in the selective expression of genes associated with proliferation and differentiation and, how gene expression in response modulates both intracellular (nuclear matrix and cytoskeleton) and extracellular (extracellular matrix) architecture. The extent to which common signaling mechanisms and regulatory events are operative in the control of proliferation and differentiation is also addressed. The book concludes by analyzing the involvement of histone modifications in the condensation of mitotic chromosomes. This book is of interest to advanced undergraduate students, as well as to graduate students and researchers in genetics, cell biology, biological chemistry, microbiology, and immunology.

An ability to control the degree of heterogeneity in cellular phenotypes may be important for cell populations to survive uncertain and ever-changing environments or make cell-fate decisions in response to external stimuli. Cells may control the degree of gene expression heterogeneity and ultimately levels of phenotypic heterogeneity by modulating promoter switching dynamics. In this thesis, I investigated various mechanisms by which heterogeneity in the expression of FLO 11 in S. cerevisiae could be generated and controlled. First, we show that two copies of the FLOJ1 locus in S. cerevisiae switch between a silenced and competent promoter state in a random and independent fashion, implying that the molecular event leading to the transition occurs in cis. Through further quantification of the effect of trans regulators on both the slow epigenetic transitions between a silenced and competent promoter state and the fast promoter transitions associated with conventional regulation of FLO11, we found different classes of regulators affect epigenetic, conventional, or both forms of regulation. Distributing kinetic control of epigenetic silencing and conventional gene activation offers cells flexibility in shaping the distribution of gene expression and phenotype within a population. Next, we demonstrate how multiple molecular events occurring at a gene's promoter could lead to an overall slow step in cis. At the FLO] 1 promoter, we show that at least two pathways that recruit histone deacetylases to the promoter and in vivo association between the region -1.2 kb from the ATG start site of the FLO11 ORF and the core promoter region are all required for a stable silenced state. To generate bimodal gene expression, the activator Msnlp forms an alternate looped conformation, where the core promoter associates with the non-coding RNA PWR1's promoter and terminator regions, located at -2.1 kb and -3.0 kb from the ATG start site of the FLO]1 ORF respectively. Formation of the active looped conformation is required for Msnlp's ability to stabilize the competent state without destabilizing the silenced state and generate a bimodal response. Our results support a model where multiple stochastic steps at the promoter are required to transition between the silenced and active states, leading to an overall slow step in cis. Finally, preliminary investigations of heterozygous diploids revealed possible transvection occurring at FLO] 1, where a silenced allele of FLO 11 appeared to transfer silencing factors to a desilenced FLO11 allele on the homologous chromosome. These observations suggest a new mechanism through which heterogeneity in FL011 expression could be further controlled, in addition to the molecular events at the FL011 promoter we elucidated previously.

There is now compelling evidence that the complexity of higher organisms correlates with the relative amount of non-coding RNA rather than the number of protein-coding genes. Previously dismissed as “junk DNA”, it is the non-coding regions of the genome that are responsible for regulation, facilitating complex temporal and spatial gene expression through the combinatorial effect of numerous mechanisms and interactions working together to fine-tune gene expression. The major regions involved in regulation of a particular gene are the 5’ and 3’ untranslated regions and introns. In addition, pervasive transcription of complex genomes produces a variety of non-coding transcripts that interact with these regions and contribute to regulation. This book discusses recent insights into the regulatory roles of the untranslated gene regions and non-coding RNAs in the control of complex gene expression, as well as the implications of this in terms of organism complexity and evolution.​

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.