The Cis-regulatory Architecture of Mammalian Photoreceptors PDF Download
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Author: Karen Ann Lawrence
Publisher:
ISBN:
Category : Electronic dissertations
Languages : en
Pages : 132
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Book Description
Crx is the principal transcription factor of the photoreceptor transcriptional network and is a key regulator of photoreceptor differentiation and survival. Mice mutant for Crx lack functional photoreceptors and are blind at birth. Mutations in human CRX are associated with several retinal diseases including autosomal dominant cone-rod dystrophy 2 and Leber's congenital amaurosis, a severe form of blindness in newborns. Given the importance of Crx in photoreceptor development and maintenance, genome-wide mapping of Crx binding sites was used to facilitate identification of photoreceptor cis-regulatory elements. ChIP-seq against Crx identified thousands of cis-regulatory regions around photoreceptor genes in adult mouse retina. Crx directly regulates downstream photoreceptor transcription factors and their target genes via a network of spatially distributed regulatory elements around each locus. Crx-bound regions act in a synergistic fashion to activate transcription and contain multiple Crx binding sites which interact in a spacing- and orientation-dependent manner to fine-tune transcript levels. Crx ChIP-seq was also performed on Nrl-/- retinas which represent an enriched source of cone photoreceptors. Comparison with the wild-type ChIP-seq dataset identified numerous rod- and cone-specific Crx-bound regions as well as many shared elements. Thus, Crx combinatorially orchestrates the transcriptional networks of both rods and cones by coordinating the expression of photoreceptor genes including most retinal disease genes. This study pinpoints thousands of non-coding regions of relevance to both Mendelian and complex retinal disease and allows prioritization of human retinal disease genes which has already resulted in identification of FAM161A and MAK, novel disease genes implicated in retinitis pigmentosa.
Author: Karen Ann Lawrence
Publisher:
ISBN:
Category : Electronic dissertations
Languages : en
Pages : 132
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Book Description
Crx is the principal transcription factor of the photoreceptor transcriptional network and is a key regulator of photoreceptor differentiation and survival. Mice mutant for Crx lack functional photoreceptors and are blind at birth. Mutations in human CRX are associated with several retinal diseases including autosomal dominant cone-rod dystrophy 2 and Leber's congenital amaurosis, a severe form of blindness in newborns. Given the importance of Crx in photoreceptor development and maintenance, genome-wide mapping of Crx binding sites was used to facilitate identification of photoreceptor cis-regulatory elements. ChIP-seq against Crx identified thousands of cis-regulatory regions around photoreceptor genes in adult mouse retina. Crx directly regulates downstream photoreceptor transcription factors and their target genes via a network of spatially distributed regulatory elements around each locus. Crx-bound regions act in a synergistic fashion to activate transcription and contain multiple Crx binding sites which interact in a spacing- and orientation-dependent manner to fine-tune transcript levels. Crx ChIP-seq was also performed on Nrl-/- retinas which represent an enriched source of cone photoreceptors. Comparison with the wild-type ChIP-seq dataset identified numerous rod- and cone-specific Crx-bound regions as well as many shared elements. Thus, Crx combinatorially orchestrates the transcriptional networks of both rods and cones by coordinating the expression of photoreceptor genes including most retinal disease genes. This study pinpoints thousands of non-coding regions of relevance to both Mendelian and complex retinal disease and allows prioritization of human retinal disease genes which has already resulted in identification of FAM161A and MAK, novel disease genes implicated in retinitis pigmentosa.
Author: Jamie C. Kwasnieski
Publisher:
ISBN:
Category : Electronic dissertations
Languages : en
Pages : 123
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Book Description
Transcription factors regulate the expression level of target genes by binding to cis-regulatory elements (CREs) present in gene promoters. The goal of my thesis research is to define the sequence components of CREs that determine transcriptional output. In order to accomplish this goal, I developed a method to measure the regulatory activity of thousands of CREs in a single experiment. In this method I insert unique barcodes in the 3'UTR of a reporter gene and multiplex expression measurements with RNA sequencing. Using this technique in explanted retinas, I determined the impact of single nucleotide variants in a mammalian promoter by measuring expression controlled by all single nucleotide variants of the Rhodopsin proximal promoter. I found that nearly all (86%) sequence variants drive significantly different activity than the wild-type promoter and that the mechanism of most variants can be interpreted as altered transcription factor binding. In addition, we found that the largest changes in expression resulted from variants located in characterized transcription factor binding site sequences. Next, I explored how combinations of binding sites drive particular levels of gene expression by utilizing a synthetic biology approach. I generated synthetic CREs composed of various combinations of binding sites found in the Rhodopsin promoter and measured the expression driven by these sequences. In this study I found that synthetic CREs containing binding sites for transcriptional activators yielded diverse expression outputs, including both activation and repression of a minimal promoter. Together, these experiments demonstrate that interactions between binding sites and dual regulation of a single binding site can produce diverse gene expression patterns. I conclude that simple cis-regulatory elements can produce complex expression outputs due to interactions between transcriptional activators and detailed quantitative models will be necessary to predict expression from these sequences.
Author: Andrew Everett Oliver Hughes
Publisher:
ISBN:
Category : Electronic dissertations
Languages : en
Pages : 152
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Book Description
Photoreceptors are light-sensitive neurons that mediate vision, and they are the most commonly affected cell type in genetic forms of blindness. In mice, there are two basic types of photoreceptors, rods and cones, which mediate vision in dim and bright environments, respectively. The transcription factors (TFs) that control rod and cone development have been studied in detail, but the cis-regulatory elements (CREs) through which these TFs act are less well understood. To comprehensively identify photoreceptor CREs in mice and to understand their relationship with gene expression, we performed open chromatin (ATAC-seq) and transcriptome (RNA-seq) profiling of FACS-purified rods and cones. We find that rods have significantly fewer regions of open chromatin than cones (as well as >60 additional cell types and tissues), and we demonstrate that this uniquely closed chromatin architecture depends on the rod master regulator Nrl. Finally, we find that regions of rod- and cone-specific open chromatin are enriched for distinct sets of TF binding sites, providing insight into the cis-regulatory grammar of these cell types.We also sought to understand how the regulatory activity of rod and cone open chromatin regions is encoded in DNA sequence. Cone-rod homeobox (CRX) is a paired-like homeodomain TF and master regulator of both rod and cone development, and CRX binding sites are by far the most enriched TF binding sites in photoreceptor CREs. The in vitro DNA binding preferences of CRX have been extensively characterized, but how well in vitro models of TF binding site affinity predict in vivo regulatory activity is not known. In addition, paired-class homeodomain TFs bind DNA as both monomers and dimers, but whether monomeric and dimeric CRX binding sites have distinct regulatory activities is not known. To address these questions, we used a massively parallel reporter assay to quantify the activity of thousands native and mutant CRX binding sites in explanted mouse retinas. These data reveal that dimeric CRX binding sites encode stronger enhancers than monomeric CRX binding sites. Moreover, the activity of half-sites within dimeric CRX binding sites is cooperative and spacing-dependent. In addition, saturating mutagenesis of 195 CRX binding sites reveals that, while TF binding site affinity and activity are moderately correlated across mutations within individual CREs, they are poorly correlated across mutations from distinct CREs. Accordingly, we show that accounting for baseline CRE activity improves the prediction of the effects of mutations in regulatory DNA from sequence-based models. Taken together, these data demonstrate that the activity of CRX binding sites depends on multiple layers of sequence context, providing insight into photoreceptor gene regulation and illustrating functional principles of homeodomain TF binding sites.
Author: G. Berlucchi
Publisher: Springer Science & Business Media
ISBN: 3642654959
Category : Medical
Languages : en
Pages : 758
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Book Description
Author: John D. Ash
Publisher: Springer Science & Business Media
ISBN: 146143209X
Category : Medical
Languages : en
Pages : 841
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Book Description
This book will contain the proceedings of the XV International Symposium on Retinal Degeneration (RD2012). A majority of those who will speak and present posters at the meeting will contribute to this volume. The blinding diseases of inherited retinal degenerations have no treatments, and age-related macular degeneration has no cures, despite the fact that it is an epidemic among the elderly, with 1 in 3-4 affected by the age of 70. The RD Symposium will focus on the exciting new developments aimed at understanding these diseases and providing therapies for them. Since most major scientists in the field of retinal degenerations attend the biennial RD Symposia, they are known by most as the “best” and “most important” meetings in the field. The volume will present representative state-of-the-art research in almost all areas of retinal degenerations, ranging from cytopathologic, physiologic, diagnostic and clinical aspects; animal models; mechanisms of cell death; candidate genes, cloning, mapping and other aspects of molecular genetics; and developing potential therapeutic measures such as gene therapy and neuroprotective agents for potential pharmaceutical therapy. While advances in these areas of retinal degenerations will be described, there will be many new topics that either were in their infancy or did not exist at the time of the last RD Symposium, RD2010. These include the role of inflammation and immunity, as well as other basic mechanisms, in age-related macular degeneration, several new aspects of gene therapy, and revolutionary new imaging and functional testing that will have a huge impact on the diagnosis and following the course of retinal degenerations, as well as to provide new quantitative endpoints for clinical trials. The retina is an approachable part of the central nervous system (CNS), and there is a major interest in neuroprotective and gene therapy for CNS diseases and neurodegenerations, in general. It should be noted that with successful and exciting initial clinical trials in neuroprotective and gene therapy, including the restoration of sight in blind children, the retinal degeneration therapies are leading the way towards new therapeutic measures for neurodegenerations of the CNS. Many of the successes recently reported in these areas of retinal degeneration sprang from collaborations established at previous RD Symposia, and many of those will be reported at the RD2010 meeting and included in the proposed volume. We anticipate the excitement of those working in the field and those afflicted with retinal degenerations will be reflected in the volume.
Author: Helga Kolb
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Author:
Publisher: ScholarlyEditions
ISBN: 1464996687
Category : Medical
Languages : en
Pages : 256
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Book Description
Eye Diseases—Advances in Research and Treatment: 2012 Edition is a ScholarlyEditions™ eBook that delivers timely, authoritative, and comprehensive information about Eye Diseases. The editors have built Eye Diseases—Advances in Research and Treatment: 2012 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about Eye Diseases in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Eye Diseases—Advances in Research and Treatment: 2012 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.
Author:
Publisher: Academic Press
ISBN: 0128148802
Category : Science
Languages : en
Pages : 541
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Book Description
Epigenetics and Regeneration compiles the first foundational reference on epigenetic mechanisms governing tissue development, repair, homeostasis, and regeneration, as well as pathways to employ these mechanisms in clinical practice and translational science. In this book, life science researchers, clinicians, and students will discover an interdisciplinary resource bringing together common themes in the field, background overviews, research methods, recent advances, and opportunities for drug discovery. Throughout this volume, special attention is paid to pre-clinical and first clinical studies aimed at increasing the regenerative potential of damaged tissues by epigenetic drugs, as well as innovative, discipline spanning strategies to enhance cell reprogramming. As an all-inclusive, evidence-based volume, Epigenetics and Regeneration will stimulate discussion and boost new research in this fascinating and impactful area of translational epigenetics. Provides a foundational overview of epigenetics in regenerative medicine Examines epigenetic components of tissue regeneration for a variety of organ systems and tissue types, as well as current attempts to employ these mechanisms in clinical practice Offers researchers, students, clinicians, and pharmacologists the tools they need to enhance tissue development, repair, homeostasis, and regeneration and explore new epigenetic therapeutic pathways Features chapter contributions from leading international researchers and clinicians in the fields of epigenetics and regenerative medicine
Author: Alexey V. Pindyurin
Publisher: Frontiers Media SA
ISBN: 2832505295
Category : Science
Languages : en
Pages : 248
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Book Description
Author:
Publisher: Academic Press
ISBN: 0128054093
Category : Medical
Languages : en
Pages : 5215
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Book Description
The Senses: A Comprehensive Reference, Second Edition, Seven Volume Set is a comprehensive reference work covering the range of topics that constitute current knowledge of the neural mechanisms underlying the different senses. This important work provides the most up-to-date, cutting-edge, comprehensive reference combining volumes on all major sensory modalities in one set. Offering 264 chapters from a distinguished team of international experts, The Senses lays out current knowledge on the anatomy, physiology, and molecular biology of sensory organs, in a collection of comprehensive chapters spanning 4 volumes. Topics covered include the perception, psychophysics, and higher order processing of sensory information, as well as disorders and new diagnostic and treatment methods. Written for a wide audience, this reference work provides students, scholars, medical doctors, as well as anyone interested in neuroscience, a comprehensive overview of the knowledge accumulated on the function of sense organs, sensory systems, and how the brain processes sensory input. As with the first edition, contributions from leading scholars from around the world will ensure The Senses offers a truly international portrait of sensory physiology. The set is the definitive reference on sensory neuroscience and provides the ultimate entry point into the review and original literature in Sensory Neuroscience enabling students and scientists to delve into the subject and deepen their knowledge. All-inclusive coverage of topics: updated edition offers readers the only current reference available covering neurobiology, physiology, anatomy, and molecular biology of sense organs and the processing of sensory information in the brain Authoritative content: world-leading contributors provide readers with a reputable, dynamic and authoritative account of the topics under discussion Comprehensive-style content: in-depth, complex coverage of topics offers students at upper undergraduate level and above full insight into topics under discussion
