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Author: Theodore Kiosses Publisher: ISBN: Category : Languages : en Pages :
Book Description
Attaining an understanding of the mechanisms underpinning development has been amongst the cardinal scientific challenges of our age. The transition from a single cell organism to the level of complexity evidenced in higher eukaryotes has been facilitated by the advent of intricate developmental networks involving a plethora of factors that synergise to allow for precise spatio-temporal expression of the proteins present in higher organisms. Development is often portrayed as a domino like cascade of events stemming from relatively uncomplicated origins that go on to branch out and form associations and interactions amongst multitudinous actors that will inexorably lead towards a higher state of order. Transcription factors occupy a central position within this tapestry of interactions. They regulate expression of the various required proteins and they provide the cues for the developmental events that will eventually shape an organism. These factors frequently remain unknown until some occurrence causes developmental processes to fail and inadvertently focus attention on the factors that facilitate development. Myotonic dystrophy is a useful paradigm of such a developmental dysfunction that has led to the discovery of a transcription factor integral to both muscle development and gonadogenesis in both Drosophila and higher eukaryotes.
Author: Theodore Kiosses Publisher: ISBN: Category : Languages : en Pages :
Book Description
Attaining an understanding of the mechanisms underpinning development has been amongst the cardinal scientific challenges of our age. The transition from a single cell organism to the level of complexity evidenced in higher eukaryotes has been facilitated by the advent of intricate developmental networks involving a plethora of factors that synergise to allow for precise spatio-temporal expression of the proteins present in higher organisms. Development is often portrayed as a domino like cascade of events stemming from relatively uncomplicated origins that go on to branch out and form associations and interactions amongst multitudinous actors that will inexorably lead towards a higher state of order. Transcription factors occupy a central position within this tapestry of interactions. They regulate expression of the various required proteins and they provide the cues for the developmental events that will eventually shape an organism. These factors frequently remain unknown until some occurrence causes developmental processes to fail and inadvertently focus attention on the factors that facilitate development. Myotonic dystrophy is a useful paradigm of such a developmental dysfunction that has led to the discovery of a transcription factor integral to both muscle development and gonadogenesis in both Drosophila and higher eukaryotes.
Author: Gregg L. Semenza Publisher: Oxford Monographs on Medical G ISBN: 9780195112399 Category : Health & Fitness Languages : en Pages : 396
Book Description
Several general principles have emerged from the study of human transcription factors. First, germline mutations in genes encoding transcription factors result in malformation syndromes in which the development of multiple body structures is affected. Second, somatic mutations involving many of the same genes contribute to tumorigenesis. Third, transcriptional regulatory mechanisms demonstrate remarkable evolutionary conservation. Fourth, prenatal development and postnatal physiology are unified by the demonstration that a single transription factor can control the proliferation of progenitor cells during development and the expression within the differentiated cells of gene products that participate in specific physiologic responses. Transcription Factors and Human Disease presents the basic science of transcriptional regulation and then describes inherited human diseases attributable to mutations in DNA sequences encoding transcription factors or their cognate binding sites. The involvement of transcription factors in somatic cell genetic diseases (cancer) and epigenetic disease (teratogenesis) is briefly discussed. The effect of specific mutations on transcription factor activity and the relationship between transcriptional dysregulation, dominant or recessive inheritance patterns, and disease pathogenesis are also explored. This book thus provides a direct connection between molecular defects in transcriptional regulation and human pathophysiology.
Author: Kenzie Daniel MacIsaac Publisher: ISBN: Category : Languages : en Pages : 150
Book Description
(Cont.) We next present a biophysically motivated framework for modeling protein-DNA interactions and show how it leads to very natural algorithms for analyzing the binding specificity of an immunoprecipitated protein, and jointly analyzing protein localization data for multiple regulators or multiple conditions. Finally, we present an analysis of transcriptional coregulator binding in a variety of mouse tissues and a method for predicting which proteins form complexes with the coregulator based purely on the sequence of the regions it binds. We detail a simple but powerful model relating regulator binding to gene expression, and show how the position of regulatory regions is of crucial importance for predicting the expression level of nearby genes.
Author: Shravan Sukumar Publisher: ISBN: Category : Languages : en Pages : 286
Book Description
Protein-DNA interactions are among the most significant intermolecular interactions in the cell, being involved in the regulation of key biological functions such as transcription, DNA replication, chromatin organization, DNA recombination and repair. Transcription Factors (TFs) play a crucial role in the upstream control of gene regulation, influencing transcription by binding to specific DNA sequences. There are several biophysical and geometric factors that determine DNA specificity in TFs - including electrostatics, hydrogen bonding, hydrophobic interactions, and DNA shape. Our approach to identifying markers of specificity combines data from high-throughput experimental assays, structural analyses and simulated data in order to understand the hierarchy of biophysical interactions in determining specificity. In this study, we investigated the role of base- and shape-readout with the aim of identifying the different affinity regimes for these interactions. Analyzing TFs belonging to several different families, we describe the concept of 'specificity anchors', which provide preferential DNA recognition even at low binding affinities. We then explored the structural basis of these specificity anchors, demonstrating a relationship with base-specific hydrogen bonds at the binding interface. We highlighted the link between specificity anchors and human disease, by showing that mutations at specificity anchors are linked to disease-associated variations in the genome. We also describe a proof-of-concept study demonstrating the ability to re-engineer specificity at the protein-DNA interface, based on the theory of specificity anchors. Further, we explored the role of different parameters of DNA geometry in determining specificity. We identified characteristic shape profiles exhibited by sequences bound at different affinity levels, and designed a comprehensive feature library to quantify these geometric properties of DNA. To study shape specificity in evolutionarily related proteins, we applied our analysis to the bZIP family, and explained the role of features of DNA shape in uniquely regulating specificity within different protein subfamilies. Using our approach, we also identified features that display evolutionary trends of specificity. This work aims at improving the understanding of the rules governing DNA specificity and identifying links to the etiology of human disease, with the ultimate goal of developing a framework to re-engineer specificity in novel DNA-binding molecules.
Author: Zheng Zuo Publisher: ISBN: Category : Electronic dissertations Languages : en Pages : 89
Book Description
Knowing the specificity of transcription factors is critical to understanding regulatory networks in cells. Using latest high-throughput sequencing technology, it becomes possible to quantify the transcription factor's specificity profile in a principled way, and therefore achieve both high accuracy and throughput, which we named Spec-seq. This method has been successfully applied to two distinct protein families, i.e., LacI family in prokaryotes and Glucocorticoid receptor in mammalian system. The lac repressor-operator system has been studied for many decades, but not with high throughput methods capable of determining specificity comprehensively. Details of its binding interaction and its selection of an asymmetric binding site have been controversial. So I employed Spec-seq to accurately determine relative binding affinities to thousands of sequences simultaneously, requiring only sequencing of bound and unbound fractions. An analysis of 2560 different DNA sequence variants, including both base changes and variations in operator length, provides a detailed view of lac repressor sequence specificity. It is found that the protein can bind with nearly equal affinities to operators of three different lengths, but the sequence preference changes depending on the length, demonstrating alternative modes of interaction between the protein and DNA. The wild type operator has an odd length causing the two monomers to bind in alternative modes, making the asymmetric operator the preferred binding site. However, two other LacI/GalR protein family members purR and Ycjw, cannot bind their operators with variable spacing. A further comparison with known and predicted motifs suggests that lac repressor may be unique in this ability. Therefore, I used site-directed mutagenesis approach to build series of lacI and purR mutants and tested their specificity profiles. It is discovered that the YQ recognition residues combined with the hinge helix loop in lac repressor are necessary and sufficient for this unique structural flexibility, even though it doesn't necessarily means alternative motif recognition. Besides its structural flexibility, I also used lac repressor as model system to investigate the specificity change under different salts concentrations and temperatures. Even though ionic strength is known to be able to modulate protein's binding affinity to its target, it shows limited impact on specificity, at least for lac repressor case. Moreover, we can successfully use Spec-seq to quantify the specificity change under different temperatures. Given lac repressor's detailed binding specificity and some other knowledge, it is possible to build a quantitative model to understand how it gets positioned onto the lac operator. In a simplified model, high specific binding energy, appropriate TF copy number, combined with DNA looping are sufficient to fulfill this job, and this could be generalized to other gene regulatory systems.
Author: Publisher: Academic Press ISBN: 0128140860 Category : Medical Languages : en Pages : 320
Book Description
Growing evidence suggests that epigenetic mechanisms play a central role in stem cell biology and are vital for determining gene expression during cellular differentiation and governing mammalian development. In Stem Cell Epigenetics, leading international researchers examine how chromatin regulation and bona fide epigenetic mechanisms underlie stem cell renewal and differentiation. Authors also explore how the diversity of cell types, including the extent revealed by single cell omic approaches, is achieved, and how such processes may be reversed or managed via epigenetic reprogramming. Topics discussed include chromatin in pluripotency, stem cells and DNA methylation, histone modifications in stem cells and differentiation, higher-order chromatin conformation in pluripotent cells, stem cells and cancer, epigenetics and disease modeling, brain organoids from pluripotent cells, transcriptional regulation in stem cells and differentiation, non-coding RNAs in pluripotency and early differentiation, and diseases caused by epigenetic alterations in stem cells. Additionally, the book discusses the potential implementation of stem cell epigenetics in drug discovery, regenerative medicine, and disease treatment. Stem Cell Epigenetics will provide researchers and physicians with a state-of-the-art map to orient across the frontiers of this fast-evolving field. Analyzes the role of epigenetics in embryonic stem cell regulation Indicates the epigenetic mechanisms involved in stem cell differentiation and highlights modifications and misregulations that may result in disease pathogenesis Examines the potential applications of stem cell epigenetics in therapeutic disease interventions and regenerative medicine, providing a foundation for researchers and physicians to bring this exciting and fast-evolving field into a clinical setting Features chapter contributions by leading international experts
Author: Michael Bate Publisher: ISBN: 9780879698997 Category : Science Languages : en Pages : 0
Book Description
The fruit fly Drosophila melanogaster offers the most powerful means of studying embryonic development in eukaryotes. New information from many different organ systems has accumulated rapidly in the past decade. This monograph, written by the most distinguished workers in the field, is the most authoritative and comprehensive synthesis of Drosophila developmental biology available and emphasizes the insights gained by molecular and genetic analysis. In two volumes, it is a lavishly illustrated, elegantly designed reference work illustrating principles of genetic regulation of embryogenesis that may apply to other eukaryotes.
Author: Theodore Kiosses
Author: Theodore Kiosses
Author: Theodore Kiosses
Author: Steven L. McKnight
Author: Gregg L. Semenza
Author: Kenzie Daniel MacIsaac
Author: Catherine E. Mitchelmore
Author: Shravan Sukumar
Author: Zheng Zuo
Author: 
Author: Michael Bate