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Author: Joshua Jaeger Wolf
Publisher:
ISBN:
Category :
Languages : en
Pages : 148
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Book Description
RNA-binding proteins can regulate the stability, localization, and translation of their target mRNAs. Post-transcriptional regulation can orchestrate dynamic changes in gene expression, and can coordinate multiple cellular processes in response to various stimuli. Filamentous growth in Saccharomyces cerevisiae is a morphogenetic switch that occurs in response to nitrogen starvation and requires alterations in cell growth, cell cycle, and cell wall functions. Tyl element retrotransposition is also induced under conditions of nitrogen starvation. I describe a role for the RNA-binding protein Khdl in regulating these two responses to environmental stress through its mRNA targets. I identified the RNA targets of Khdl using in vivo crosslinking and immunoprecipitation (CLIP), combined with deep sequencing. This produced a high-resolution map of Khdl binding sites across the transcriptome, and provided unprecedented insight into its biological functions. Khdl regulates multiple post-transcriptional regulatory loops to coordinate the components of filamentous growth and Tyl retrotransposition. Although similar mechanisms were known to transcriptionally regulate these processes, the posttranscriptional coordination is a novel discovery. The feed-forward regulation that Khdl confers on FLO11, which encodes a protein required for filamentous growth, enables asymmetric expression between mother and daughter cells to switch between filamentous and yeast form growth. In this thesis, I describe regulation of gene expression by RNA-binding proteins, methods to identify their target transcripts and recognition sequences, the KH domain, known functions of Khdl, and the phenotypes it coordinates. My work represents the first application of CLIP to budding yeast, and the growing understanding of RNA-binding proteins in this organism facilitated the placement of Khdl into its posttranscriptional regulatory network. While many questions remain regarding the role Khdl plays in regulating cellular activities, this thesis addresses its direct role in key processes.
Author: Joshua Jaeger Wolf
Publisher:
ISBN:
Category :
Languages : en
Pages : 148
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Book Description
RNA-binding proteins can regulate the stability, localization, and translation of their target mRNAs. Post-transcriptional regulation can orchestrate dynamic changes in gene expression, and can coordinate multiple cellular processes in response to various stimuli. Filamentous growth in Saccharomyces cerevisiae is a morphogenetic switch that occurs in response to nitrogen starvation and requires alterations in cell growth, cell cycle, and cell wall functions. Tyl element retrotransposition is also induced under conditions of nitrogen starvation. I describe a role for the RNA-binding protein Khdl in regulating these two responses to environmental stress through its mRNA targets. I identified the RNA targets of Khdl using in vivo crosslinking and immunoprecipitation (CLIP), combined with deep sequencing. This produced a high-resolution map of Khdl binding sites across the transcriptome, and provided unprecedented insight into its biological functions. Khdl regulates multiple post-transcriptional regulatory loops to coordinate the components of filamentous growth and Tyl retrotransposition. Although similar mechanisms were known to transcriptionally regulate these processes, the posttranscriptional coordination is a novel discovery. The feed-forward regulation that Khdl confers on FLO11, which encodes a protein required for filamentous growth, enables asymmetric expression between mother and daughter cells to switch between filamentous and yeast form growth. In this thesis, I describe regulation of gene expression by RNA-binding proteins, methods to identify their target transcripts and recognition sequences, the KH domain, known functions of Khdl, and the phenotypes it coordinates. My work represents the first application of CLIP to budding yeast, and the growing understanding of RNA-binding proteins in this organism facilitated the placement of Khdl into its posttranscriptional regulatory network. While many questions remain regarding the role Khdl plays in regulating cellular activities, this thesis addresses its direct role in key processes.
Author: Zdravko Lorkovic
Publisher: CRC Press
ISBN: 149871336X
Category : Science
Languages : en
Pages : 174
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Book Description
Gene expression in eukaryotes is regulated at different levels, which need to be coordinated to implement the information in the genome. Now it is clear that post-transcriptional regulation of gene expression such as pre-mRNA splicing, mRNA transport, editing, turnover and translation are as important as the control of transcription. In all aspects
Author:
Publisher: Academic Press
ISBN: 0123973481
Category : Science
Languages : en
Pages : 993
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Book Description
The genetic, molecular, and cellular mechanisms of neural development are essential for understanding evolution and disorders of neural systems. Recent advances in genetic, molecular, and cell biological methods have generated a massive increase in new information, but there is a paucity of comprehensive and up-to-date syntheses, references, and historical perspectives on this important subject. The Comprehensive Developmental Neuroscience series is designed to fill this gap, offering the most thorough coverage of this field on the market today and addressing all aspects of how the nervous system and its components develop. Particular attention is paid to the effects of abnormal development and on new psychiatric/neurological treatments being developed based on our increased understanding of developmental mechanisms. Each volume in the series consists of review style articles that average 15-20pp and feature numerous illustrations and full references. Volume 1 offers 48 high level articles devoted mainly to patterning and cell type specification in the developing central and peripheral nervous systems. - Series offers 144 articles for 2904 full color pages addressing ways in which the nervous system and its components develop - Features leading experts in various subfields as Section Editors and article Authors - All articles peer reviewed by Section Editors to ensure accuracy, thoroughness, and scholarship - Volume 1 sections include coverage of mechanisms which: control regional specification, regulate proliferation of neuronal progenitors and control differentiation and survival of specific neuronal subtypes, and controlling development of non-neural cells
Author: Erik Dassi
Publisher: Humana
ISBN: 9781071618530
Category : Science
Languages : en
Pages : 0
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Book Description
This volume presents the most recent advances in techniques for studying the post-transcriptional regulation of gene expression (PTR). With sections on bioinformatics approaches, expression profiling, the protein and RNA interactome, the mRNA lifecycle, and RNA modifications, the book guides molecular biologists toward harnessing the power of this new generation of techniques, while also introducing the data analysis skills that these high-throughput techniques require. Written for the highly successful Methods in Molecular Biology series, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and up-to-date, Post-Transcriptional Gene Regulation, Third Edition serves as a versatile resource for researchers studying post-transcriptional regulation by both introducing the most recent techniques and providing a comprehensive guide to their implementation. Chapter 6 is available open access under a Creative Commons Attribution 4.0 International License via link.springer.com.
Author: Bronwyn Ayla Lucas
Publisher:
ISBN:
Category :
Languages : en
Pages : 155
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Book Description
RNA binding proteins (RBPs) are key regulators of gene expression that, by interacting with specific RNAs, can impact their splicing, localization, translation and decay. Staufen proteins are RBPs that are conserved through metazoan evolution, and can simultaneously bind both double-stranded RNAs (dsRNAs) and diverse proteins. These properties, together with its presence in the nucleus, cytoplasm and at the endoplasmic reticulum (ER), has made it a versatile regulatory protein. In this thesis I explore three distinct contexts wherein Staufen1 has been co-opted during mammalian evolution to regulate gene expression. The first example pursues the Maquat-lab finding that mammalian Staufen1 (STAU1) binds dsRNA structures formed between primate-specific Alu short interspersed elements (SINEs) in humans and between rodent-specific B or ID (B/ID) SINEs in mice. When these duplexes are present in mRNA 3'-untranslated regions (3'-UTRs), STAU1 binding promotes Staufen-mediated decay (SMD). We hypothesized that gene regulation resulting from SINE insertion might have been similarly adaptive in separate mammalian lineages, leading to parallel evolution of the Staufen network by independent exaptation of SINEs. To explore this hypothesis, we identified and confirmed orthologous gene pairs with 3'-UTR SINEs that have been independently exapted in mouse and humans for SMD control of myoblast metabolism. Expanding to other species we demonstrated that SINE-directed SMD likely emerged in both primate and rodent lineages>25 million years ago. This work reveals a novel mechanism for the convergent evolution of post-transcriptional gene regulatory networks in mammals by species-specific SINE transposition and SMD. Another consequence of STAU1 binding to duplexes formed between inverted Alu repeats (IRAlus) in mRNA 3'-UTRs is to promote the escape from nuclear retention. While some mRNAs harboring 3'-UTR IRAlus can be retained in the nucleus by interaction with the paraspeckle protein p54nrb, other 3'-UTR IRAlus do not promote nuclear retention but do promote mRNA translation. The diverse consequences of 3'-UTR Alus imply the existence of different, as yet undefined subcategories. To reach a global understanding of the contribution of 3'-UTR Alus to mRNA localization, translation and decay we undertook to characterize the nucleocytoplasmic distribution, translation and abundance of the 3'-UTR Alu element-containing transcriptome using the isoform-specific RNA seq method, READS+. Using this method uncovered 3'-UTR features that correlate with mRNA localization and distinguish a subset of IRAlus-containing mRNAs, for which the mRNA export is regulated by STAU1. We made an additional and unexpected finding that 3'-UTR length is a determinant of mRNA localization, independent of Alu content. STAU1 also binds intramolecular duplexes in ER-localized mRNAs, including the ER stress-responsive transcript XBP1. Under ER stress, this transcript is known to undergo cytoplasmic cleavage and ligation resulting in a translational frameshift and production of a potent transcription factor that activates ER stress-responsive genes. I have show that knockdown of Staufen1 reduced the production of spliced XBP1 in response to ER stress without a concomitant increase in unspliced XBP1, which, together with my finding that STAU1 co-immunoprecipitates with the RNA ligase RTCB, implicates Staufen1 as a regulator of the ligation step, rather than the cleavage step, of XBP1 splicing. Depletion of Staufen1 also reduced the abundance of XBP1 mRNA in unstressed cells, signifying that STAU1 is additionally required for the maintenance of XBP1 mRNA, and as such the sensitivity to ER stress. This poses the possibility that STAU1 promotes the re-ligation by RTCB after cleavage of XBP1 mRNA at a single site. Interestingly, while the endonuclease that catalyzes the cleavage step of XBP1 mRNA splicing is conserved in eukaryotes, RTCB catalyzes the ligation step of XBP1 mRNA splicing only in metazoans, co-occurring with the emergence of Staufen proteins. Taken together, the capacity of STAU1 to bind to different dsRNA sequences and structures has enabled the convergent evolution of SINE-directed Staufen-mediated mRNA decay in human and mouse, promotes the expression of IRAlus-containing mRNAs and the cellular resilience to ER stress.
Author: Roberto Giambruno
Publisher: Frontiers Media SA
ISBN: 2889743691
Category : Science
Languages : en
Pages : 123
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Book Description
Dr. Nicolas Lux Fawzi is a member of the Scientific Advisory Board of Dewpoint Therapeutics LLC. All other Topic Editors declare no competing interests with regards to the Research Topic.
Author: Daniel Michael Klass
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
We are on the threshold of a new era in our understanding of that fantastic feat of regulation at the core of life itself--gene expression. The rapid pace of new developments in genome-wide, high-throughput technologies has allowed us unprecedented access to observe multiple stages of the gene expression program for nearly the entire genome. This has revealed a widespread discordance between mRNA abundance and protein abundance for many genes whose expression changes in response to environmental stimuli, and a significant coordination of post-transcriptional regulation for specific sets of related mRNAs at the levels localization, translation, decay, and the noise in gene expression. Despite this evidence suggesting the existence of a coordinated regulatory framework that potentially affects the fate of every mRNA in the cell, our efforts to discern the underlying structure and regulatory themes are hindered by an incomplete understanding of RNA-protein interactions. To advance our comprehension of post-transcriptional regulation, we developed new tools to identify which proteins bind to RNA, which of those bind concurrently, which RNAs are bound by a given protein, and where each protein binds on each RNA. Using our proteomic tools we discovered hundreds unexpected RNA binding proteins, uncovered new RNA binding domains, identified widespread, concurrent binding with several RNA binding proteins, and inferred functional information from the simultaneous binding partners of several RNA binding proteins. We used our genomic, sequencing-based tools to systematically interrogate a large set of diverse RNA binding proteins and we discerned new themes from the resulting data. This revealed significant differences in function, localization, and regulation among the proteins encoded by the targets of a given RNA binding protein based on binding position. These results suggest that the functional consequences of the RBP-RNA interaction are determined not only by whether an mRNA is bound by an RBP but also by the position of the binding site within the mRNA and its relation to the other RBPs that bind the same mRNA. Overall, we found evidence of an extensive regulatory framework involving hundreds of RNA binding proteins, encompassing nearly the entire transcriptome, and extending our understanding of the RNA-protein interactions at the heart of post-transcriptional regulation.
Author:
Publisher:
ISBN: 9781071608340
Category : Gene expression
Languages : en
Pages :
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Author: Gerrit Martin Daubner
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Author: Melissa L. Wilbert
Publisher:
ISBN: 9781303678172
Category :
Languages : en
Pages : 195
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Book Description
The field of stem cell biology is moving forward at an unprecedented rate in part due to the discovery that adult somatic cells can be reprogrammed to a pluripotent stem cell like state. The factors first used in reprogramming were transcription factors such as OCT4, SOX2 and NANOG, and the RNA-binding protein LIN28. Like transcription factors, RNA-binding proteins (RBPs) control vast networks of gene targets to direct pathways in the cell; however, for RBPs this is accomplished through post-transcriptional binding to RNA transcripts. Only recently has it been possible to survey the transcripome-wide RNA binding interactions of a protein, through isolation of endogenous RBP-RNA complexes paired with high-throughput sequencing technologies. Using cross-linking followed by immunoprecipitation of protein-RNA complexes and sequencing of isolated transcripts (CLIP-seq) we have identified LIN28 binding sites throughout the human transcriptome. The resolution of our data enabled us to define characteristic LIN28 mRNA interactions at GGAGA rich motifs within unpaired regions of hairpin loops. This binding pattern mimics interactions described for LIN28 binding within let-7 family microRNA precursors. The ability to consider LIN28 targets on a global scale enabled the identification of RNA processing factors, in particular splicing factors, as prevalent functions encoded by LIN28 bound RNAs. This information helped to accurately predict which of the thousands of LIN28 targets would be functionally regulated. We found evidence that LIN28 increases the protein production of splicing factors resulting in massive rearrangement of RNA transcripts through downstream splicing changes. Subsequent transcriptome-wide studies of LIN28 have confirmed these findings despite differences in the pool of direct targets defined by individual reports. Taken together, we understand that LIN28 can bind to a wide network of transcripts, influencing development through these direct RNA interactions and via downstream effects. Combinatorial approaches in the study of LIN28 using changes in RNA-levels, protein production, strength of CLIP-seq binding, and ontological classification of gene targets have extracted meaningful information about mechanisms of LIN28 regulation. We expect that application of similar methods will enable studies of additional RBPs. For example, in the study of other stem cell enriched proteins like the IGFII-mRNA binding proteins (IG2BP or IMP). Furthermore, the overlap of other regulatory networks hold promise of highlighting novel hubs of regulation that may be exploited in reprogramming or directed differentiation. The next step is to use these connections to explain how genetic changes within an individual can affect RBP function and result in disease. We can apply in vitro modeling of development using directed differentiation to iteratively test how the connection of LIN28 to its target transcripts impacts its role in development and disease.
