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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.
Mammalian SWI/SNF (also called BAF) ATP-dependent chromatin remodeling complexes are essential for formation of the pluripotent cells of the early embryo, and are also crucial for the self-renewal and pluripotency of mouse embryonic stem cells (ESCs). To understand the molecular mechanism of BAF complexes in regulating the chromatin of pluripotent stem cells, we performed both proteomic and genomic studies of endogenous complexes in ESCs. Proteomic studies reveal that ESCs express distinctive BAF complexes (esBAF), and this specialized subunit composition is required for ESC maintenance and pluripotency. High-resolution genome-wide mapping of the core ATPase subunit, Brg, using ChIP-Seq technology indicates that esBAF is a core component of the pluripotent transcriptional network. This is consistent with findings that esBAF interacts both physically and genetically with key regulators of pluripotency such as Stat3, Oct4 and Sox2. In addition, esBAF is critical for Stat3-mediated gene activation and repression in mESCs in response to Leukemia Inhibitory Factor (LIF), the cytokine that maintains mESCs in a self-renewing state. Brg maintains open accessibility of Stat3 target sites to allow continuous binding of Stat3 in response to LIF signaling, and prevents the expansion of Polycomb activity and the inappropriate deposition of the silencing mark H3K27me3 at both Stat3 targets and other sites. We propose that one integral mechanism of esBAF action in maintaining pluripotency is to maintain Stat3 responsiveness in ESCs by regulating the accessibility of its target sites. The role of BAF complexes in self-renewal and differentiation extend to adult multipotent stem cells. Using mouse adult hematopoietic development as a model, we show that Brg is required for the transition of quiescent long-term hematopoietic stem cells (LT-HSCs) to their downstream progenitors, and for the multilineage differentiation of transit amplifying hematopoietic progenitors. Hence, we propose that chromatin remodeling is generally required for the function and maintenance of stem cells by the regulation of their specialized chromatin landscape.
Abstract: The process of gastrulation results in the three-layered embryo and is characterized by a precise context- and time-specific regulation of transcriptional activity. The early expressed T-box transcription factor EOMES plays a crucial role by conducting the specification of mesoderm and endoderm and preventing the specification of neuroectodermal derivates. The exact molecular mechanisms of this first cell-lineage specification are still unknown. Latest findings indicate that the presence of EOMES at ME genes results in an open chromatin state while binding to already accessible NE enhancers has repressive effects. These changes in chromatin are in accordance to an association of EOMES with chromatin remodeling complexes found in mass spectrometry analysis. Particularly several components of the multi-subunit complexes BAF and NuRD emerged from a large spectrum of potential interaction partners. Mammalian BAF complex, member of the SWI/SNF family, is mainly considered to create an accessible chromatin state and allows active gene expression. In contrast, activity of the NuRD complex mostly results in a closed chromatin formation and transcriptional repression. Both ATP-dependent chromatin remodeling complexes have a wide cellular distribution and were shown to have indispensable roles in development by cooperating with tissue-specific co-regulators. This project aimed to better characterize the T-box factor induced chromatin remodeling by identifying the interacting subunit(s) of BAF and NuRD complex. The experimental setting included transfection of HEK293T cells and P19CL6 cells, co-immunoprecipitation and analysis on Western Blot. As specific interactors of EOMES, BAF60B of the BAF complex and MBD3 of the NuRD complex were identified. The recruitment of chromatin remodeling complexes via unique subcomponents is a possible mechanism to specifically influence transcriptional activity on target genes. Hereby, the cooperation of EOMES and BAF complex would result in accessible chromatin at ME genes, while interaction with NuRD complex would prevent expression of NE and pluripotency genes. Furthermore, the characteristic appearance of EOMES protein as three bands on Western blots was analyzed by mass spectrometry (MS). Additional bands are larger than the expected molecular weight of EOMES, thus I focused on post-translational modifications. A preliminary MS analysis revealed ubiquitination as possible modification. If ubiquitination has a functional impact on EOMES requires further studies. In summary, this project gives further proof of direct interaction of EOMES and chromatin remodeling complexes BAF and NuRD and serves a model where chromatin remodeling importantly contributes to the specific functions of T-box factors. The detailed effects of this cooperation on transcriptional chromatin-based and T-box dependent regulation during the first cell lineage decision needs further investigation
In the human central nervous system, astrocytes vastly outnumber neurons and regulate a host of physiological processes critical to its function. Astrocytes form a functional syncytium tiling the brain with minimal overlap between individual cells. This anatomical organization implies that a balanced numbers of neurons and astrocytes must be generated during brain development. In spite of this, very little is known about the molecular events governing proliferation and differentiation in the astroglial lineage that culminate in the establishment of adequate numbers of astrocytes. In recent ...
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.
Stem cells are the building blocks for all other cells in an organism. The human body has about 200 different types of cells and any of those cells can be produced by a stem cell. This fact emphasizes the significance of stem cells in transplantational medicine, regenerative therapy and bioengineering. Whether embryonic or adult, these cells can be used for the successful treatment of a wide range of diseases that were not treatable before, such as osteogenesis imperfecta in children, different forms of leukemias, acute myocardial infarction, some neural damages and diseases, etc. Bioengineering, e.g. successful manipulation of these cells with multipotential capacity of differentiation toward appropriate patterns and precise quantity, are the prerequisites for successful outcome and treatment. By combining in vivo and in vitro techniques, it is now possible to manage the wide spectrum of tissue damages and organ diseases. Although the stem-cell therapy is not a response to all the questions, it provides more and more answers every day. Stem Cells and Tissue Engineering is a concise review on the functional, phenotypic, regenerative, transplantational and curative aspects of a stem cell’s entity. It is critical and encouraging at the same time, providing truthful and appropriate samples from the practice and research that can lead toward optimal use of this immense source of adjuvant and curative therapy in human pathology. Written by a clinician and a researcher, who are currently teaching what they are doing, it is recommended as a teaching tool along with an original textbook.
Stem cell science has the potential to impact human reproductive medicine significantly - cutting edge technologies allow the production and regeneration of viable gametes from human stem cells offering potential to preciously infertile patients. Written by leading experts in the field Stem Cells in Reproductive Medicine brings together chapters on the genetics and epigenetics of both the male and female gametes as well as advice on the production and regeneration of gene cells in men and women, trophoblasts and endometrium from human embryonic and adult stem cells. Although focussing mainly on the practical elements of the use of stem cells in reproductive medicine, the book also contains a section on new developments in stem cell research. The book is essential reading for reproductive medicine clinicians, gynecologists and embryologists who want to keep abreast of practical developments in this rapidly developing field.
Chromatin Signaling and Diseases covers the molecular mechanisms that regulate gene expression, which govern everything from embryonic development, growth, and human pathologies associated with aging, such as cancer. This book helps researchers learn about or keep up with the quickly expanding field of chromatin signaling. After reading this book, clinicians will be more capable of explaining the mechanisms of gene expression regulation to their patients to reassure them about new drug developments that target chromatin signaling mechanisms. For example, several epigenetic drugs that act on chromatin signaling factors are in clinical trials or even approved for usage in cancer treatments, Alzheimer's, and Huntington's diseases. Other epigenetic drugs are in development to regulate various class of chromatin signaling factors. To keep up with this changing landscape, clinicians and doctors will need to stay familiar with genetic advances that translate to clinical practice, such as chromatin signaling. Although sequencing of the human genome was completed over a decade ago and its structure investigated for nearly half a century, molecular mechanisms that regulate gene expression remain largely misunderstood. An emerging concept called chromatin signaling proposes that small protein domains recognize chemical modifications on the genome scaffolding histone proteins, facilitating the nucleation of enzymatic complexes at specific loci that then open up or shut down the access to genetic information, thereby regulating gene expression. The addition and removal of chemical modifications on histones, as well as the proteins that specifically recognize these, is reviewed in Chromatin Signaling and Diseases. Finally, the impact of gene expression defects associated with malfunctioning chromatin signaling is also explored. Explains molecular mechanisms that regulate gene expression, which governs everything from embryonic development, growth, and human pathologies associated with aging Educates clinicians and researchers about chromatin signaling, a molecular mechanism that is changing our understanding of human pathology Explores the addition and removal of chemical modifications on histones, the proteins that specifically recognize these, and the impact of gene expression defects associated with malfunctioning chromatin signaling Helps researchers learn about the quickly expanding field of chromatin signaling
Cell Polarity in Development and Disease, Volume 154 in the Methods in Cell Biology series, highlights new advances in the field, with this new volume presenting interesting chapters on a variety of timely topics, including Cell polarity in the protist-to-animal transition, Polarized actin networks in development: Case studies from Drosophila, Protein clustering and cell polarization, Polarity in the Drosophila female germline, Context Matters: Mechanisms governing epithelial polarization in C. elegans, Epithelial polarity in the fly: Principles and diversity, Polarizing epithelial expulsion and expulsion driven by mispolarization, The Role of Apical-Basal Polarization in the Mammalian First Cell Fate Decision, and much more. Provides the authority and expertise of leading contributors from an international board of authors Presents the latest release in the Methods in Cell Biology series Updated release includes the latest information on Cell Polarity in Development and Disease