Transcriptional Control of Lineage Differentiation in Immune Cells PDF Download
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Author: Wilfried Ellmeier
Publisher: Springer
ISBN: 3319073958
Category : Medical
Languages : en
Pages : 334
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Book Description
Insights into the regulation of immune cell lineage differentiation and specification as well as into the control of lineage integrity, stability and plasticity are of fundamental importance to understanding innate and adaptive immune responses. In this volume, leading experts provide an up-to-date and comprehensive overview of recent advances in the transcriptional control mechanisms and transcription factor networks that regulate these processes in a variety of different immune cell lineages. The chapters cover the regulation of T versus B cell lineage choice, discuss early B cell development and pre-B cell leukemia prevention, address transcriptional control mechanisms during the differentiation, in regulatory T cells and iNKT cells, detail genomic switches in helper cell fate choice and plasticity and highlight the role of the BTB-zinc finger family of transcription factors in T cells. Moreover, the chapters discuss transcriptional networks in DCs, NK cells and in innate lymphoid cells. Together, the reviews illustrate key transcriptional control mechanisms that regulate the development and function of immune cells and demonstrate the impressive advances made over the last decade.
Author: Wilfried Ellmeier
Publisher: Springer
ISBN: 3319073958
Category : Medical
Languages : en
Pages : 334
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Book Description
Insights into the regulation of immune cell lineage differentiation and specification as well as into the control of lineage integrity, stability and plasticity are of fundamental importance to understanding innate and adaptive immune responses. In this volume, leading experts provide an up-to-date and comprehensive overview of recent advances in the transcriptional control mechanisms and transcription factor networks that regulate these processes in a variety of different immune cell lineages. The chapters cover the regulation of T versus B cell lineage choice, discuss early B cell development and pre-B cell leukemia prevention, address transcriptional control mechanisms during the differentiation, in regulatory T cells and iNKT cells, detail genomic switches in helper cell fate choice and plasticity and highlight the role of the BTB-zinc finger family of transcription factors in T cells. Moreover, the chapters discuss transcriptional networks in DCs, NK cells and in innate lymphoid cells. Together, the reviews illustrate key transcriptional control mechanisms that regulate the development and function of immune cells and demonstrate the impressive advances made over the last decade.
Author: Nikki Ruoxi Kong
Publisher:
ISBN:
Category :
Languages : en
Pages : 195
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Book Description
Gene expression is critical for the development, patterning, and homeostasis of the organism. Precise temporal and spatial regulation of gene expression at the level of transcription requires a large network of sequence-specific factors, general transcription factors, co-factors, and epigenetic regulators. Malignancies of specific tissues often arise from perturbation of various gene expression levels. Hematopoiesis is one of the most sensitive biological processes to mis-regulation of transcription. To generate all blood cell types from embryonic development throughout the lifetime of the organism, hematopoiesis requires an intricate balance between the maintenance of a permanent stem cell pool and differentiation of multi-potent stem cells into cell types with unique functions. To generate a terminally differentiated, functional immune cell, multiple lineage-restricting steps are involved, with each governed by a specific transcription program. Therefore, gene expression regulation in hematopoietic differentiation is particularly important for an organism to properly develop, maintain oxygen transport to all tissues, and fight against infections. Furthermore, because of detailed understanding of how to isolate cells at different stages and lineages of hematopoietic differentiation, it provides an important model to study the development and differentiation of other adult tissues. Hematopoietic stem cells can be driven to differentiate along three main lineages: myeloid, erythroid, and lymphoid. Despite the discoveries of several transcription factors for specific lineages of hematopoietic differentiation, understanding the gene expression program that allow stem cells to make the decision to initiate lymphoid development still remains incomplete. For example, how is the preinititation complex of transcription (PIC) recruited to the gene promoters? Additionally, how are interactions, if any, coordinated among various sequence-specific factors that were identified via gene-by-gene knockout (KO) approaches? To form the PIC at any gene promoter, transcription factor (TF) IIA, B, D, E, F, and H, and RNA polymerase II (Pol II) must coordinate their promoter-binding and enzymatic activities. TFIID, especially, is important for promoter recognition. As a multi-subunit complex containing TATA-box binding protein (TBP) and 13-14 TBP-associated factors (TAFs), TFIID binds to sequences in the proximal promoter and allows the recruitment of other TFs and Pol II. Previously thought to be invariant from one cell type to another, recently tissue-specific roles for certain TAFs have been uncovered. TAF4B is one of the first TAFs found to have cell-specific expression, since it was identified in human B cells {Dikstein:1996wk}, though a role for its function in hematopoiesis has remained elusive. I used a Taf4b KO mouse line to study its function in both myeloid and lymphoid differentiation. I found that Taf4b KO mice were able to generate myeloid and lymphoid progenitors as well as their wild-type (WT) littermates. Furthermore, both of these types of progenitors from Taf4b KO mice can terminally differentiate into mature cells as well as those from WT mice. Finally, TAF4B-null cells are as competent as heterozygous cells (equivalent to WT in terms of Taf4b expression) to reconstitute the hematopoietic compartment of lethally irradiated mice in all cell lineages tested. In conclusion, TAF4B is dispensable in both myeloid and B cell differentiation. This could be due to TAF4B's high sequence homology with TAF4A. Alternatively, TAF4B can play a role in fine-tuning expression levels of certain B cell or myeloid-specific genes, together with another transcription factor, which cannot be uncovered in a KO mouse approach. I have made a TAF4B-specific polyclonal antibody that can be used to identify its transcriptional targets, as well as identify any potential interaction partners. Though the basal machinery does not seem to play a role in hematopoietic lineage determination, sequence-specific factors have long been implicated in this process. A study using an inducible hematopoietic-specific KO mouse line found that myocyte enhancer factor 2c (MEF2C) is necessary for multi-potent progenitors to differentiate into the lymphoid lineage {StehlingSun:2009df}. Through a candidate approach, I have identified early B cell factor 1 (EBF1) to be a specific interacting partner of MEF2C. Together, they co-occupy and functionally co-activate many B cell specific genes. When MEF2C is depleted in mice, the animals had reduced B cell gene expression as well as increased myeloid gene expression, consistent with MEF2C's role as a lineage fate regulator. I have identified and confirmed several B cell-specific genes that are co-regulated by EBF1 and MEF2C through a genome-wide survey of their binding via chromatin immunoprecipitation followed by exonuclease treatment and deep-sequencing (ChIP-exo). Furthermore, I found that p38 MAPK is the pathway through which MEF2C is phosphorylated and activated to drive B cell differentiation. When phosphorylated, MEF2C prefers to bind its co-activator EBF1, and not its co-repressor HDAC7. Taken together, the results presented in this thesis elucidated the mechanism of activation, binding partners, and downstream targets by which MEF2C is able to regulate lymphoid-specific differentiation. This study contributes to understanding how transcriptional regulation of genes can drive progenitor cells to differentiate down a particular lineage, and provide a novel mechanism for a transcription repressor to switch to an activator during cellular differentiation.
Author: Keiko Ozato
Publisher: Frontiers Media SA
ISBN: 2889637239
Category :
Languages : en
Pages : 149
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Book Description
Transcription depends on an ordered sequence of events, starting with (i) setting of the enhancer and chromatin environment, (ii) assembly of DNA binding and general transcription factors, (iii) initiation, elongation, processing of mRNA and termination, followed by (iv) creation of epigenetic marks and memory formation. Highlighting the importance of these activities, more than 10% total genes are dedicated to regulating transcriptional mechanisms. This area of research is highly active and new insights are continuously being added to our knowledge. Cells of the immune system have unique features of gene regulation to support diverse tasks required for innate and adaptive immunity. Innate immunity involves the recognition of external infectious and noxious agents as well as internal cancer cell components, and the elimination of these agents by non-specific mechanisms. Adaptive immunity involves gene rearrangement to achieve highly specific T and B cell responses, imparting the capability of self and non-self discrimination. This requires transcription and epigenetic regulation. Adaptive immunity also employs epigenetic memory, enabling recapitulation of prior transcription. Recent advances in nuclear architecture, chromatin structure, and transcriptional regulation have provided new insights into immune responses. The increased understanding of these molecular mechanisms is now affording opportunities to improve therapeutic strategies for various diseases.
Author:
Publisher: CSHL Press
ISBN: 0879695692
Category : Medical
Languages : en
Pages : 621
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Book Description
Provides a dialogue on the nature of the membrane signals and intracytoplasmic events that provoke immunity. The debate ranges over biochemistry, physiology, molecular genetics, as well as classical cellular immunology. Input came from over 70 of the world's leading investigators.
Author: Jonathan Soboloff
Publisher: CRC Press
ISBN: 149870509X
Category : Medical
Languages : en
Pages : 258
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Book Description
T cells play a vital role mediating adaptive immunity, a specific acquired resistance to an infectious agent produced by the introduction of an antigen. There are a variety of T cell types with different functions. They are called T cells, because they are derived from the thymus gland. This volume discusses how T cells are regulated through the operation of signaling mechanisms. Topics covered include positive and negative selection, early events in T cell receptor engagement, and various T cell subsets.
Author: Jianmei Wu Leavenworth
Publisher: Frontiers Media SA
ISBN: 2889744736
Category : Medical
Languages : en
Pages : 244
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Book Description
Topic Editor Dr. Lewis Shi received financial support from Varian Medical System, Inc. The other Topic Editors declare no competing interests with regard to the Research Topic subject.
Author: Rémy Bosselut
Publisher: Humana
ISBN: 9781493928088
Category : Medical
Languages : en
Pages : 0
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Book Description
This volume provides simple and accessible experiment protocols to explore thymus biology. T-Cell Development: Methods and Protocols is divided into three parts presenting short reviews on T cell development, analysis strategies, protocols for cell preparation, flow cytometry analyses, and multiple aspects of thymocyte biology. As a volume in the highly successful Methods in Molecular Biology series, chapters contain introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible protocols, and tips on troubleshooting and avoiding known pitfalls. Concise and easy-to-use, T-Cell Development: Methods and Protocols aims to ensure successful results in the further study of this vital field.
Author: Miaoqing Fang
Publisher:
ISBN:
Category :
Languages : en
Pages : 125
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Book Description
The adaptive immune system is an extraordinarily diverse inventory comprised of highly specialized cells, the differentiation of which requires numerous lineage specifications at various developmental stages. The precise control of immune cell differentiation and the delicate balance of their population composition are crucial for effective protection against infectious environmental agents, without triggering autoimmune responses or allergies. It is therefore important to understand at the molecular level in individual cells how lineage commitment is regulated. I explored the heterogeneous gene expression during the lineage specification of single T helper cells, by quantitatively measuring mRNA and protein levels. I have discovered a paradigm of cell lineage specification governed by the signaling interplay between extracellular cues and intracellular transcriptional factors, where the strength of extracellular signaling dominates over the intracellular signaling components. In the presence of extracellular cues, T helper cells stochastically acquire any intermediate Thl/Th2 states. The states of T helper cells can be gradually tuned by depriving availability of extracellular cytokines, which are produced stochastically by a small subpopulation of cells. When extracellular cues are removed, the weak intracellular signaling network reveals its effect, leading to classic mutual exclusion of antagonistic transcriptional factors.
Author: Ananda L. Roy
Publisher:
ISBN:
Category : Immunology
Languages : en
Pages : 144
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Book Description
The process of generating differentiated cell types performing specific effector functions from their respective undifferentiated precursors is dictated by extracellular signals and the recipient cell's ability to transmit those signals to effect changes in cellular functions. One major mechanism for bringing about such changes is at the level of transcription. Thus, inducing transcription of previously silent genes and suppressing active genes in response to the extracellular signal can result in acquiring new functions by the cells. The transcriptional machinery, comprising of RNA Polymerase II and associated general transcription factors, assemble at the core promoter of eukaryotic protein coding genes. The rate and/or stability of formation of this machinery dictate the transcriptional regulation of the corresponding gene, which can be at the level of chromatin regulation as well as enhancer-promoter communication. Such coordinated temporal and spatial regulation of gene expression in response to specific signals determines lineage differentiation, cellular proliferation and development. Every event in the life cycle of a lymphocyte is modulated by the signals they receive. For instance, expression of the B cell antigen receptor (BCR) on the surface of B cells is a hallmark of various stages of B cell development--signaling via the BCR is important both during early/antigen independent (tonic) and late/antigen dependent phases of development. Despite the established requirement for BCR signaling during various phases of B cell maturation, how BCR signaling connects to chromatin changes and downstream transcriptional pathways in each step of development remains poorly understood. Similar questions also remain in other cells of the immune system. Moreover, how the enhancers communicate to the promoters in a stage specific fashion and in the context of chromatin also remain unclear. Chromatin modifiers are generally present and active in most cell types. How could then there be differences in chromatin architecture dependent on a particular stage of development? The B (and T) lymphocytes also perform a unique developmental program because they have an unparalleled genetic makeup--the genetic loci that encode their cell surface receptors are in an 'unrearranged" or "germline" configuration during the early stages of development. Thus, they not only express stage specific genes and transcription factors during each developmental stage, they need to undergo rearrangement of their cognate receptor loci in a strictly ordered fashion to generate a pool of receptor proteins, each capable of recognizing a specific antigen, which they encounter at a much later step. Hence, there must be a strict negotiation between the recombination machinery and the transcriptional machinery at every developmental step of the way. Importantly, along the way, the B cells expressing receptors capable of recognizing self-antigens must be eliminated to avoid autoimmune responses and only those cells capable of recognizing foreign-antigens are preserved to reach peripheral organs where they eventually meet pathogens. How are these processes coordinately regulated in a stage specific fashion and what role does chromatin play? Are the rules of engagement different in innate versus adaptive immune responses? Here we seek to address some of these questions and provide our current understanding of signal-induced chromatin and transcriptional regulation of the immune system
Author: Robert M. Samstein
Publisher:
ISBN:
Category :
Languages : en
Pages : 266
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Book Description
Regulatory T (Treg) cells are critical for control of immune responses and thus maintenance of immune homeostasis in a variety of inflammatory conditions. The transcription factor Foxp3 is necessary and sufficient for Treg cell lineage development both in the thymus and the periphery and their ability to suppress immune responses. Deficiency of Foxp3 or Treg regulation results in widespread inflammation in mice and humans highlighting its essential role. However, how Treg cells function to limit inflammation in a variety of settings is poorly understood. The work described herein attempts in three studies to elucidate some of the details of how and where regulatory T cells function. In the gut, IL-10 activation of STAT3 signalling is shown to be essential for Treg cell control of Th17 inflammation and a resulting colitis suggesting that Tregs respond to and amplify existing negative regulatory circuits. Using DNase-seq and ChIP-seq Foxp3 is shown to predominantly utilize preexisting or TCR-signalling driven enhancers supporting a model of Foxp3 exploitation of a preformed enhancer landscape in order to direct Treg cell differentiation and function. Lastly, extra-thymically generated Treg cells are shown to be important for maternal fetal tolerance and the mechanisms necessary for their differentiation appear to have evolved in placental mammals. Taken together, these studies provide further insight into regulatory T cell function and offer the potential for therapeutic development in a variety of disease settings.
