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Five leaders in the field of mammalian preimplantation embryo development provide their own perspectives on key molecular and cellular processes that mediate lineage formation during the first week of life. The first cell-fate decision involves the formation of the pluripotent inner cell mass (ICM) and extraembryonic trophectoderm (TE). The second cell-fate choice encompasses the transformation of ICM into extraembryonic primitive endoderm (PE) and pluripotent epiblast. The processes, which occur during the period of preimplantation development, serve as the foundation for subsequent developmental events such as implantation, placentation, and gastrulation. The mechanisms that regulate them are complex and involve many different factors operating spatially and temporally over several days to modulate embryonic chromatin structure, impose cellular polarity, and direct distinct gene expression programs in the first cell lineages.
The activation of tissue specific genes relies upon the precise orchestration of a number of events that result in the initiation of transcription upon lineage specification. This process is heavily dictated by the chromatin environment both at the promoter and distal sequences, as well as by the availability of transcription factors necessary for activation. A critical role is played at distal regulatory sequences, which often are the first sites to be engaged by key regulatory proteins. This interaction often promotes a chromatin environment that is necessary for the activation of the gene and results in the recruitment of additional sequence specific factors and a direct interaction with the promoter to initiate transcription. Understanding the properties of enhancer elements for tissue specific genes is important for a clear understanding of the mechanisms of activation. A number of studies have shown that enhancers are marked long before the activation of the gene takes place, in some cases as early as the embryonic stem cell stage. A detailed study described an unmethylated window within the enhancer of the Ptcra locus. Further analysis showed the enhancer mark to be regulated by sequence specific binding factors. These studies lacked the appropriate chromatin environment, which we know to be important. Here we use bacterial artificial chromosome containing the Ptcra locus to demonstrate that the enhancer mark persists in a chromatin context but is not regulated in the manner described in a non-native chromatin context. We then expand our studies to global tissue specific gene expression in order to understand more broadly the regulatory properties the define tissue specific genes. Parsing the mechanisms that drive tissue specific gene expression is critical for an understanding of pluripotency and tissue specificity. Here we use deep chromatin RNA-sequencing to accurately quantify the transcriptome of pluripotent stem cells and four primary differentiated cell types - E14.5 cortical neurons, CD4+ CD8+ thymocytes, bone marrow-derived macrophages and hepatocytes, in mouse. We define tissue specific genes with the broadest dynamic range in expression and define the chromatin properties at their promoters. Separating tissue specific genes with the largest dynamic range in expression allowed us to uncover cell type specific differences in the fundamental promoter properties.
The neural crest is a remarkable embryonic population of cells found only in vertebrates and has the potential to give rise to many different cell types contributing throughout the body. These derivatives range from the mesenchymal bone and cartilage comprising the facial skeleton, to neuronal derivatives of the peripheral sensory and autonomic nervous systems, to melanocytes throughout the body, and to smooth muscle of the great arteries of the heart. For these cells to correctly progress from an unspecifi ed, nonmigratory population to a wide array of dynamic, differentiated cell types-some of which retain stem cell characteristics presumably to replenish these derivatives-requires a complex network of molecular switches to control the gene programs giving these cells their defi ning structural, enzymatic, migratory, and signaling capacities. This review will bring together current knowledge of neural crest-specifi c transcription factors governing these progressions throughout the course of development. A more thorough understanding of the mechanisms of transcriptional control in differentiation will aid in strategies designed to push undifferentiated cells toward a particular lineage, and unraveling these processes will help toward reprogramming cells from a differentiated to a more naive state. Table of Contents: Introduction / AP Genes / bHLH Genes / ETS Genes / Fox Genes / Homeobox Genes / Hox Genes / Lim Genes / Pax Genes / POU Domain Genes / RAR/RXR Genes / Smad Genes / Sox Genes / Zinc Finger Genes / Other Miscellaneous Genes / References / Author Biographies
Recent scientific breakthroughs, celebrity patient advocates, and conflicting religious beliefs have come together to bring the state of stem cell researchâ€"specifically embryonic stem cell researchâ€"into the political crosshairs. President Bush's watershed policy statement allows federal funding for embryonic stem cell research but only on a limited number of stem cell lines. Millions of Americans could be affected by the continuing political debate among policymakers and the public. Stem Cells and the Future of Regenerative Medicine provides a deeper exploration of the biological, ethical, and funding questions prompted by the therapeutic potential of undifferentiated human cells. In terms accessible to lay readers, the book summarizes what we know about adult and embryonic stem cells and discusses how to go about the transition from mouse studies to research that has therapeutic implications for people. Perhaps most important, Stem Cells and the Future of Regenerative Medicine also provides an overview of the moral and ethical problems that arise from the use of embryonic stem cells. This timely book compares the impact of public and private research funding and discusses approaches to appropriate research oversight. Based on the insights of leading scientists, ethicists, and other authorities, the book offers authoritative recommendations regarding the use of existing stem cell lines versus new lines in research, the important role of the federal government in this field of research, and other fundamental issues.
Long-Range Control of Gene Expression covers the current progress in understanding the mechanisms for genomic control of gene expression, which has grown considerably in the last few years as insight into genome organization and chromatin regulation has advanced. Discusses the evolution of cis-regulatory sequences in drosophila Includes information on genomic imprinting and imprinting defects in humans Includes a chapter on epigenetic gene regulation in cancer
Eggs of all animals contain mRNAs and proteins that are supplied to or deposited in the egg as it develops during oogenesis. These maternal gene products regulate all aspects of oocyte development, and an embryo fully relies on these maternal gene products for all aspects of its early development, including fertilization, transitions between meiotic and mitotic cell cycles, and activation of its own genome. Given the diverse processes required to produce a developmentally competent egg and embryo, it is not surprising that maternal gene products are not only essential for normal embryonic development but also for fertility. This review provides an overview of fundamental aspects of oocyte and early embryonic development and the interference and genetic approaches that have provided access to maternally regulated aspects of vertebrate development. Some of the pathways and molecules highlighted in this review, in particular, Bmps, Wnts, small GTPases, cytoskeletal components, and cell cycle regulators, are well known and are essential regulators of multiple aspects of animal development, including oogenesis, early embryogenesis, organogenesis, and reproductive fitness of the adult animal. Specific examples of developmental processes under maternal control and the essential proteins will be explored in each chapter, and where known conserved aspects or divergent roles for these maternal regulators of early vertebrate development will be discussed throughout this review. Table of Contents: Introduction / Oogenesis: From Germline Stem Cells to Germline Cysts / Oocyte Polarity and the Embryonic Axes: The Balbiani Body, an Ancient Oocyte Asymmetry / Preparing Developmentally Competent Eggs / Egg Activation / Blocking Polyspermy / Cleavage/ Mitosis: Going Multicellular / Maternal-Zygotic Transition / Reprogramming: Epigenetic Modifications and Zygotic Genome Activation / Dorsal-Ventral Axis Formation before Zygotic Genome Activation in Zebrafish and Frogs / Maternal TGF-β and the Dorsal-Ventral Embryonic Axis / Maternal Control After Zygotic Genome Activation / Compensation by Stable Maternal Proteins / Maternal Contributions to Germline Establishment or Maintenance / Perspective / Acknowledgments / References
This book provides an entry point into Systems Biology for researchers in genetics, molecular biology, cell biology, microbiology and biomedical science to understand the key concepts to expanding their work. Chapters organized around broader themes of Organelles and Organisms, Systems Properties of Biological Processes, Cellular Networks, and Systems Biology and Disease discuss the development of concepts, the current applications, and the future prospects. Emphasis is placed on concepts and insights into the multi-disciplinary nature of the field as well as the importance of systems biology in human biological research. Technology, being an extremely important aspect of scientific progress overall, and in the creation of new fields in particular, is discussed in 'boxes' within each chapter to relate to appropriate topics. 2013 Honorable Mention for Single Volume Reference in Science from the Association of American Publishers' PROSE Awards Emphasizes the interdisciplinary nature of systems biology with contributions from leaders in a variety of disciplines Includes the latest research developments in human and animal models to assist with translational research Presents biological and computational aspects of the science side-by-side to facilitate collaboration between computational and biological researchers
This open access textbook leads the reader from basic concepts of chromatin structure and function and RNA mechanisms to the understanding of epigenetics, imprinting, regeneration and reprogramming. The textbook treats epigenetic phenomena in animals, as well as plants. Written by four internationally known experts and senior lecturers in this field, it provides a valuable tool for Master- and PhD- students who need to comprehend the principles of epigenetics, or wish to gain a deeper knowledge in this field. After reading this book, the student will: Have an understanding of the basic toolbox of epigenetic regulation Know how genetic and epigenetic information layers are interconnected Be able to explain complex epigenetic phenomena by understanding the structures and principles of the underlying molecular mechanisms Understand how misregulated epigenetic mechanisms can lead to disease