Mammalian Cis-Acting RNA Sequence Elements PDF Download
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Author: Irina Vlasova-St Louis
Publisher:
ISBN:
Category : Medicine
Languages : en
Pages :
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Book Description
Cis-acting regulatory sequence elements are sequences contained in the 3' and 5' untranslated region, introns, or coding regions of precursor RNAs and mature mRNAs that are selectively recognized by a complementary set of one or more trans-acting factors to regulate posttranscriptional gene expression. This chapter focuses on mammalian cis-acting regulatory elements that had been recently discovered in different regions: pre-processed and mature. The chapter begins with an overview of two large networks of mRNAs that contain conserved AU-rich elements (AREs) or GU-rich elements (GREs), and their role in mammalian cell physiology. Other, less conserved, cis-acting elements and their functional role in different steps of RNA maturation and metabolism will be discussed. The molecular characteristics of pathological cis-acting sequences that rose from gene mutations or transcriptional aberrations are briefly outlined, with the proposed approach to restore normal gene expression. Concise models of the function of posttranscriptional regulatory networks within different cellular compartments conclude this chapter.
Author: Irina Vlasova-St Louis
Publisher:
ISBN:
Category : Medicine
Languages : en
Pages :
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Book Description
Cis-acting regulatory sequence elements are sequences contained in the 3' and 5' untranslated region, introns, or coding regions of precursor RNAs and mature mRNAs that are selectively recognized by a complementary set of one or more trans-acting factors to regulate posttranscriptional gene expression. This chapter focuses on mammalian cis-acting regulatory elements that had been recently discovered in different regions: pre-processed and mature. The chapter begins with an overview of two large networks of mRNAs that contain conserved AU-rich elements (AREs) or GU-rich elements (GREs), and their role in mammalian cell physiology. Other, less conserved, cis-acting elements and their functional role in different steps of RNA maturation and metabolism will be discussed. The molecular characteristics of pathological cis-acting sequences that rose from gene mutations or transcriptional aberrations are briefly outlined, with the proposed approach to restore normal gene expression. Concise models of the function of posttranscriptional regulatory networks within different cellular compartments conclude this chapter.
Author: Katla Kristjánsdóttir
Publisher:
ISBN:
Category :
Languages : en
Pages : 282
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Book Description
Regulating the precise rate of protein production from each protein-coding gene is a fundamental process of all cellular life. While transcriptional regulation plays a large role in determining final protein levels, post-transcriptional events can also make substantial contributions. In mammals, the majority of the cis-regulatory information that controls post-transcriptional events is located within a transcript’s 3′ untranslated region (3′ UTR). The cis-regulatory sequence elements (cis-elements) found within 3′ UTRs are bound by trans-acting factors, mainly RNA binding proteins and non-coding RNAs, which in turn interact with the core decay and translation machineries to modulate mRNA decay or protein synthesis rates. Though a large number of cis-elements have been identified, many questions remain about their distribution and interactions. In addition, the contribution of parameters whose function is independent of their sequence, such as the length of the 3′ UTR, to gene regulation is poorly understood. Numerous studies have established that typical 3′ UTRs contain multiple discrete cis-elements, yet the typical density of elements within 3′ UTRs is unclear. Moreover, examples exist describing consequential interactions between cis-elements, either cooperative or inhibitory. However, the extent to which such interactions are a general paradigm for cis-elements remains to be determined. By performing a systematic study of the regulatory sequences within two conserved mammalian 3′ UTRs, those of Hmga2 and PIM1, I determined that both 3′ UTRs contain a high density of cis-elements (at minimum 6 and 12 per kb, respectively) spread across the entire 3′UTR. Importantly, the vast majority of the cis-elements function independently of neighboring elements. Additionally, despite the overall repressive effect of the 3′ UTRs, I found that many regulatory cis-elements enhance gene expression, rather than repressing it. I hypothesize that the enhancing cis-elements counteract a repressive effect of 3′ UTR length. In a second study, I explored the effect of 3′ UTR length on gene expression using, as 3′UTR mimics, randomly-generated, nucleotide-composition matched, sequences of varying lengths. Long 3′ UTRs have previously been identified as targets of an mRNA surveillance mechanism called nonsense-mediated decay (NMD). In this study, I discovered a novel role for 3′ UTR length in triggering an NMD-independent decay pathway in human cell lines. Reporter transcripts with random 3′ UTR mimics as short as 400 nucleotides were repressed by this pathway, with the repression growing stronger with increasing length. While the mechanism of this novel pathway remains to be elucidated, I have determined that it affects the decay rate of mature mRNAs in a deadenylation-independent manner. Overall, by determining the density and extent of interactions of cis-element within example mammalian 3′ UTRs and by identifying a novel role for 3′ UTR length in regulating gene expression, this work furthers our understanding of fundamental aspects of 3′ UTR-mediated gene regulation. ...
Author: Mathias Munschauer
Publisher: Springer
ISBN: 3319162535
Category : Technology & Engineering
Languages : en
Pages : 140
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Book Description
The work reported in this book represents an excellent example of how creative experimentation and technology development, complemented by computational data analysis, can yield important insights that further our understanding of biological entities from a systems perspective. The book describes how the study of a single RNA-binding protein and its interaction sites led to the development of the novel ‘protein occupancy profiling’ technology that for the first time captured the mRNA sequence space contacted by the ensemble of expressed RNA binders. Application of protein occupancy profiling to eukaryotic cells revealed that extensive sequence stretches in 3’ UTRs can be contacted by RBPs and that evolutionary conservation as well as negative selection act on protein-RNA contact sites, suggesting functional importance. Comparative analysis of the RBP-bound sequence space has the potential to unravel putative cis-acting RNA elements without a priori knowledge of the bound regulators. Here, Dr. Munschauer provides a comprehensive introduction to the field of post-transcriptional gene regulation, examines state-of-the-art technologies, and combines the conclusions from several journal articles into a coherent and logical story from the frontiers of systems-biology inspired life science. This thesis, submitted to the Department of Biology, Chemistry and Pharmacy at Freie Universität Berlin, was selected as outstanding work by the Berlin Institute for Medical Systems Biology at the Max-Delbrueck Center for Molecular Medicine, Germany.
Author: Ingo Potrykus
Publisher: Springer Science & Business Media
ISBN: 3642792472
Category : Science
Languages : en
Pages : 370
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Book Description
Author: Thomas Dandekar
Publisher: Springer Science & Business Media
ISBN: 3642562981
Category : Science
Languages : en
Pages : 234
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Book Description
RNA Motifs and Regulatory Elements is the new edition of the successful book, "Regulatory RNA". It alerts the reader to the importance of regulatory RNA elements for the many different areas of cellular life. The computational and experimental methods and tools to search for new interesting regulatory RNA structures are explained and compared. The knowledge on regulatory RNA structures and elements already available is concisely summarized as well as catalogued. In addition, interesting RNA elements are analyzed in detail regarding their dynamics, regulation, and as a dominant topic of current resarch in molecular biology, including areas such as RNA mediated regulation of gene-expression, DNA/RNA chip data, and ribozymes, splicing, or telomerases in aging. Medical implications are also covered. Future progress and research are finally outlined.
Author: Gun Woo Byeon
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
Translation can be critically and pervasively regulated in a transcript-specific manner to modulate protein synthesis. However, it is poorly understood which and how cis-regulatory features of the messenger ribonucleic acid (mRNA) encode variable transcript-specific translation rates to impact spatiotemporal gene expression patterns. Here, I address the role of 5' untranslated (5' UTR) in regulating mRNA translation in vertebrate species. In the first part of the dissertation, I explore the phenomenon of extreme non-coding sequence conservation in vertebrate genomes at the level of RNA function in 5' UTRs. Extreme conservation is a fascinating mystery in comparative genomics in which sequence conservation, at levels often greater than coding regions with invariant polypeptide sequences, stretches on for hundreds of nucleotides in the non-coding regions of the genome. While extreme conservation has been extensively studied for its role in transcriptional regulation, its RNA-level function in translational regulation remains largely unknown. This work reveals the role of extremely conserved 5' UTRs in translational regulation of genes linked to the emergence of essential developmental features in vertebrate species. Extremely conserved 5' UTRs are found to contain cis-elements that promote cell-type specific non-canonical translation initiation. As these elements function as RNA molecules, an understanding of their structures is essential. To this end, I develop in-cell mutate-and-map (icM2), a methodology that maps RNA structure using high-throughput mutational analysis inside cells. icM2 maps the ensemble of multiple conformations in an extremely conserved 5' UTR which is found to be important for its translational regulatory function. I find that active RNA structural remodeling inside cells by RNA helicase activity maintains the relative balance of the conformations. Furthermore, cellular structural remodeling occurs frequently in the most conserved regions of the 5' UTRs. I propose a structural explanation for extreme conservation at the level of RNA and highlight the importance of comparative genomics and of RNA structure in understanding 5' UTR function and evolution. In the second part of the dissertation, I explore the genome-wide role of mammalian ribosome expansion segments (ES) in interacting with 5' UTRs to regulate mRNA translation. ESs are eukaryote-specific insertions to the ribosomal ribonucleic acid (rRNA). They are positioned mostly at the exterior surface of the ribosome structure, extending from the core of the ribosome like flexible tentacles. It has been recently shown that the mammalian ES9S in 18S rRNA directly interacts with a Hox gene 5' UTR element to promote its translation. Direct rRNA-mRNA interaction is not a widely recognized paradigm for translation initiation in eukaryotes. However, addressing the potential genome-wide significance of such a mechanism mediated by ribosome ESs and mRNA 5' UTRs is challenging. Since rRNAs are transcribed from tandem repeats of ribosomal DNA units that can range up to hundreds of thousands of copies, it has not been possible to directly manipulate ESs in most species. To solve this problem, I develop VELCRO-IP RNA-seq: variable expansion segment-ligand chimeric ribosome immunoprecipitation RNA sequencing. VELCRO-IP RNA-seq interrogates the interaction of a ribosome ES with mRNA elements genome-wide by combining yeast genetics, in vitro biochemical pull-down and high-throughput sequencing. By applying VELCRO-IP RNA-seq on mammalian ES9S, hundreds of mRNA regions that interact with the ribosome via specific interaction with the ES are identified. Furthermore, the 5' UTR targets of ES9S are found to promote non-canonical translation. A number of short k-mers that have Watson-Crick complementary to ES9S subsequences are overrepresented in its targets, suggesting potential importance of canonical base-pairing. These results provide evidence for the usage of direct mRNA-rRNA interaction as a mechanism of translation initiation on a wider scale than previously imagined for vertebrate species. Finally, in the last chapter, I discuss how my findings can shape future investigations into the remaining unanswered questions on 5' UTR regulation of translation. Altogether, this dissertation takes us a step closer to the ultimate goal of deciphering the code for translational regulation.
Author: John F. Atkins
Publisher: Springer Science & Business Media
ISBN: 0387893822
Category : Science
Languages : en
Pages : 473
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Book Description
The literature on recoding is scattered, so this superb book ?lls a need by prov- ing up-to-date, comprehensive, authoritative reviews of the many kinds of recoding phenomena. Between 1961 and 1966 my colleagues and I deciphered the genetic code in Escherichia coli and showed that the genetic code is the same in E. coli, Xenopus laevis, and guinea pig tissues. These results showed that the code has been c- served during evolution and strongly suggested that the code appeared very early during biological evolution, that all forms of life on earth descended from a c- mon ancestor, and thus that all forms of life on this planet are related to one another. The problem of biological time was solved by encoding information in DNA and retrieving the information for each new generation, for it is easier to make a new organism than it is to repair an aging, malfunctioning one. Subsequently, small modi?cations of the standard genetic code were found in certain organisms and in mitochondria. Mitochondrial DNA only encodes about 10–13 proteins, so some modi?cations of the genetic code are tolerated that pr- ably would be lethal if applied to the thousands of kinds of proteins encoded by genomic DNA.
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: Altuna Akalin
Publisher: CRC Press
ISBN: 1498781861
Category : Mathematics
Languages : en
Pages : 463
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Book Description
Computational Genomics with R provides a starting point for beginners in genomic data analysis and also guides more advanced practitioners to sophisticated data analysis techniques in genomics. The book covers topics from R programming, to machine learning and statistics, to the latest genomic data analysis techniques. The text provides accessible information and explanations, always with the genomics context in the background. This also contains practical and well-documented examples in R so readers can analyze their data by simply reusing the code presented. As the field of computational genomics is interdisciplinary, it requires different starting points for people with different backgrounds. For example, a biologist might skip sections on basic genome biology and start with R programming, whereas a computer scientist might want to start with genome biology. After reading: You will have the basics of R and be able to dive right into specialized uses of R for computational genomics such as using Bioconductor packages. You will be familiar with statistics, supervised and unsupervised learning techniques that are important in data modeling, and exploratory analysis of high-dimensional data. You will understand genomic intervals and operations on them that are used for tasks such as aligned read counting and genomic feature annotation. You will know the basics of processing and quality checking high-throughput sequencing data. You will be able to do sequence analysis, such as calculating GC content for parts of a genome or finding transcription factor binding sites. You will know about visualization techniques used in genomics, such as heatmaps, meta-gene plots, and genomic track visualization. You will be familiar with analysis of different high-throughput sequencing data sets, such as RNA-seq, ChIP-seq, and BS-seq. You will know basic techniques for integrating and interpreting multi-omics datasets. Altuna Akalin is a group leader and head of the Bioinformatics and Omics Data Science Platform at the Berlin Institute of Medical Systems Biology, Max Delbrück Center, Berlin. He has been developing computational methods for analyzing and integrating large-scale genomics data sets since 2002. He has published an extensive body of work in this area. The framework for this book grew out of the yearly computational genomics courses he has been organizing and teaching since 2015.
Author: Lutz Nover
Publisher: Springer Science & Business Media
ISBN: 3540480374
Category : Science
Languages : en
Pages : 279
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Book Description
The control of plant gene expression at the transcriptional level is the main subject of this volume. Genetics, molecular biology and gene technology have dramatically improved our knowledge of this event. The functional analysis of promoters and transcription factors provides more and more insights into the molecular anatomy of initiation complexes assembled from RNA polymerase and the multiplicity of helper and control proteins. Formation of specific DNA-protein complexes - activating or repressing transcription - is the crux of developmental or environmental control of gene expression. The book presents an up-to-date, critical overview of this rapidly advancing field.
