Phenotypic Switching

Phenotypic Switching: Implications in Biology and Medicine provides a comprehensive examination of phenotypic switching across biological systems, including underlying mechanisms, evolutionary significance, and its role in biomedical science. Contributions from international leaders discuss conceptual and theoretical aspects of phenotypic plasticity, its influence over biological development, differentiation, biodiversity, and potential applications in cancer therapy, regenerative medicine and stem cell therapy, among other treatments. Chapters discuss fundamental mechanisms of phenotypic switching, including transition states, cell fate decisions, epigenetic factors, stochasticity, protein-based inheritance, specific areas of human development and disease relevance, phenotypic plasticity in melanoma, prostate cancer, breast cancer, non-genetic heterogeneity in cancer, hepatitis C, and more. This book is essential for active researchers, basic and translational scientists, clinicians, postgraduates and students in genetics, human genomics, pathology, bioinformatics, developmental biology, evolutionary biology and adaptive opportunities in yeast. Thoroughly addresses the conceptual, experimental and translational aspects that underlie phenotypic plasticity Emphasizes quantitative approaches, nonlinear dynamics, mechanistic insights and key methodologies to advance phenotypic plasticity studies Features a diverse range of chapter contributions from international leaders in the field

Candida albicans is a major fungal pathogen of humans. It is a harmless commensal in healthy individuals, but it can cause serious infections in immune-compromised hosts. C. albicans undergoes a meta-stable and reversible switch between two distinct cell types known as white and opaque. The role of white-opaque switching in the biology of C. albicans was originally not well understood. We discovered an unexpected relationship between white-opaque switching and the sexual cycle of C. albicans . The mating type locus of C. albicans (MTL) encodes transcriptional regulatory proteins that regulate mating. We demonstrated that two MTL -encoded homeodomain proteins, a 1 and alpha2, work together to repress white-opaque switching in C. albicans . The observations that the MTL locus controlled both mating and white-opaque switching led us to hypothesize that opaque cells played a role in mating. Indeed, we found that opaque cells mate one million times more efficiently than do white cells. Additionally, opaque cells, but not white cells, developed specialized mating projections when exposed to mating pheromone. Thus, opaque cells are a specialized mating form of C. albicans . As white cells are generally more robust in a mammalian host than opaque cells, this strategy allows the organism to survive the rigors of life within a mammalian host, while generating a small population of mating-competent cells. The mechanism that controls white-opaque switching is not well understood. To better understand the mechanism, we investigated the regulation of white-opaque switching by a 1-alpha2. We demonstrated that a 1-alpha2 regulates white-opaque switching by destabilizing opaque cells, and we monitored gene expression during the transition from opaque to white using DNA microarrays. We used a candidate approach to identify additional regulators of white-opaque switching among genes enriched for their expression in the opaque phase. We identified two potent positive regulators of white-opaque switching: the opaque-specific transcriptional regulatory proteins Czf1 and Naf1. We also further investigated the role of Efg1, a previously identified regulator of white-opaque switching, and found that efg1/efg1 mutants were unable to bypass a 1-alpha2 repression of switching. Finally, we determined the epistatic and regulatory relationships between Efg1, Czf1 and Naf1.

A large number of terrestrial microbial lives thrive in extremes of environmental conditions, including extremes of pressure, temperature, salinity, pH, and a combination of them. For example, all the marine biomass thrive at high hydrostatic pressure depending on depth. The temperature in the ocean can be very high near the hydrothermal vents and salinity and pH depends on the composition of salt in the surrounding areas. On the surface, hot springs, lakes and geysers provide high temperature conditions, while many places are permafrost regions with subzero temperatures. There is an emerging body of work on the viability, genomics, and metagenomics of these organisms, also called extremophiles due to their love for extremes of physicochemical conditions. However, these studies only provide a small window into their adaptation. A better insight into their adaptation to these conditions can be obtained by investigating the effect of these environments on cellular processes of mesophiles, organisms that are not adapted to extremes. Usually, extremes of environmental conditions lead to stresses on mesophilic cells, and therefore, application of these environments may reveal the bottleneck cellular processes that are prone to fail. The effect of pressure, temperature, and salinity on various cellular processes including metabolisms, growth, cell division, and gene expression of a mesophilic bacterium, Escherichia coli was studied. This work provides a quantitative picture of these cellular processes of phenotypes obtained under different extremes, and sets a foundation for long-term laboratory evolution of a mesophilic bacterium to the extremes of environmental conditions. Furthermore, the results presented here are also useful in assessing the kind of microbial lifeforms that may exist elsewhere in our solar system, such as Mars, Europa, Ceres, and Enceladus, where the presence of liquid water is known.

In order to determine the host signals and fungal signaling pathways that control the white-GUT switch and drive commensalism, we developed an in vitro system to induce switching behavior and screened a library of C. albicans signaling mutants. We identified three fungal signaling pathways (Hog1, Rim101, and PKA), previously associated with other morphological transitions, which promote GUT cell formation. Together these studies help to understand how C. albicans' phenotypic plasticity influences its interactions with the mammalian host.

Gene expression is a stochastic biological processes that controls the different phenotypes of an organism depending on the environment. High-resolution single cell measurements show that genetically identical cells can be different from each other even in a homogeneous environment, leading a spectrum of phenotypes with different cellular fitnesses that can reversibly switch between phenotypes. How population-level properties emerge from single cell behavior and how mutants emerge and spread in such populations is unclear. In this thesis, we developed mathematical models to study (i) the effect of time-delay needed for a mutation in a regulator gene influence an effector protein and the long term population fitness, (ii) how optimum population fitness behaves as a function of the growth rates of the various phenotypes for different durations in fluctuating environments. Our work shows a paradoxical outcome of evolution where mutations in a regulator gene interact with gene network dynamics and evolutionary dynamics, giving rise to permanent decrease in population fitness. In the other scenario of fluctuating environments, a previously predicted optimum exists for wider parameter regime if the environmental durations are long and narrow regime for short environmental durations. We also find that a mutant, which randomly evolved to match its phenotypic switching rates with environmental switching rates, can sweep the population if the predicted optimum matches with the assumed one, but not otherwise.

The process of Epithelial-Mesenchymal-Transition (EMT) is known to result in a phenotype change in cells from a proliferative state to a more invasive state. EMT has been reported to drive the metastatic spread of various cancers and has also been associated with drug resistance to cytotoxics and targeted therapeutics. Recently phenotype switching akin to EMT has been reported in non-epithelial cancers such as metastatic melanoma. This process involves changes in EMT-Transcription Factors (EMT-TFs), suggesting that phenotype-switching may be common to several tumour types. It remains unclear as to whether the presence of both Epilthelial-like and Mesenchymal-like cells are a pre-requisite for phenotype switching within a tumour, how this heterogeneity is regulated, and if alteration of cell phenotype is sufficient to mediate migratory changes, or whether drivers of cell migration result in an associated phenotype switch in cancer cells. Similarly it has yet to be clarified if cells in an altered phenotype can be refractory to drug therapy or whether mediators of drug resistance induce a concurrent phenotypic change. Little is known today about the underlying genetic, epigenetic and transient changes that accompany this phenotypic switch and about the role for the tumor micro-environment in influencing it. Hence this is currently an area of speculation and keen interest in the Oncology field with wide-ranging translational implications. In this Frontiers Research Topic, we discuss our current understanding of these concepts in various cancer types including breast cancer, colorectal cancer and metastatic melanoma. This topic covers how these processes of cellular and phenotypic plasticity are regulated and how they relate to cancer initiation, progression, dormancy, metastases and response to cytotoxics or targeted therapies.

This text gives an overview of the fundamental aspects of molecular fungal development in one comprehensive volume, highlighting different elements in the maturational and reproductive cycles of selected fungal taxa.

This book is about the growth and differentiation processes underlying the growth and differentia of filamentous fungi. The impetus for this work tion of fungi and that it provides the reader with stems from our perception that the coverage of adequate source references for further information. this highly diverse and important group of organ It is estimated conservatively that there are more isms has been neglected in recent years, despite than 1. 5 million species of fungi - more than five many significant advances in our understanding of times the number of vascular plants and second the underlying mechanisms of growth. This situ only in diversity to the insects. The extreme ation contrasts with the treatment of Saccharomyces diversity of form in the fungi has always been a cerevisiae, for example, which because of its ideal source of inspiration for mycologists. This book is properties for genetic analyses, has established concerned mainly with those systems that have itself as the model eukaryote for the analysis of the been well characterized from the biochemical, cell cycle, and basic studies of biochemical and physiological or genetic points of view. Although genetic regulation. This book does not deal with it has not been possible to illustrate the breadth of the detailed growth phYSiology of S.

Handbook of Epigenetics: The New Molecular and Medical Genetics, Second Edition, provides a comprehensive analysis of epigenetics, from basic biology, to clinical application. Epigenetics is considered by many to be the new genetics in that many biological phenomena are controlled, not through gene mutations, but rather through reversible and heritable epigenetic processes. These epigenetic processes range from DNA methylation to prions. The biological processes impacted by epigenetics are vast and encompass effects in lower organisms and humans that include tissue and organ regeneration, X-chromosome inactivation, stem cell differentiation, genomic imprinting, and aging. The first edition of this important work received excellent reviews; the second edition continues its comprehensive coverage adding more current research and new topics based on customer and reader reviews, including new discoveries, approved therapeutics, and clinical trials. From molecular mechanisms and epigenetic technology, to discoveries in human disease and clinical epigenetics, the nature and applications of the science is presented for those with interests ranging from the fundamental basis of epigenetics, to therapeutic interventions for epigenetic-based disorders. Timely and comprehensive collection of fully up-to-date reviews on epigenetics that are organized into one volume and written by leading figures in the field Covers the latest advances in many different areas of epigenetics, ranging from basic aspects, to technologies, to clinical medicine Written at a verbal and technical level that can be understood by scientists and college students Updated to include new epigenetic discoveries, newly approved therapeutics, and clinical trials