The Double-stranded RNA-binding Protein Staufen1 Negatively Regulates Skeletal Muscle Differentiation PDF Download
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Author: Marie-Laure Blais-Crepeau
Publisher:
ISBN: 9780494866610
Category :
Languages : en
Pages :
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Book Description
Author: Marie-Laure Blais-Crepeau
Publisher:
ISBN: 9780494866610
Category :
Languages : en
Pages :
Get Book Here
Book Description
Author: Marie Laure Blais-Crépeau
Publisher:
ISBN:
Category : Muscles
Languages : en
Pages :
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Book Description
Staufen1 is a double-stranded RNA-binding protein known to be involved in the transport, localization, decay and increased translation of some mRNAs. The goal of the present study is to determine the role of Staufen1 during myogenic differentiation by characterizing the effects of Staufen1 over-expression in C2C12 cells. Immunofluorescence experiments revealed that Staufen1 over-expression causes a decrease in the fusion and differentiation indices and leads to the formation of myotubes with significantly fewer nuclei. We show, by western blot and qRT-PCR, that the protein expression of MyoD, myogenin and MyHC and the mRNA expression of MyoD, myogenin, Mef2A, Mef2C and p35 are significantly decreased during differentiation when Staufen1 is over-expressed. We then found that c-myc protein expression was increased during proliferation but that its mRNA expression remained unchanged. In this study we propose that Staufen1 negatively regulates skeletal muscle differentiation through the posttranscriptional regulation of c-myc, Mef2A, Mef2C and p35 transcripts.
Author: Tara Crawford Parks
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Over the past decade several converging lines of evidence have highlighted the importance of post-transcriptional events in skeletal muscle. This level of regulation is controlled by multi-functional RNA-binding proteins and trans-acting factors. In fact, several RNA-binding proteins are implicated in neuromuscular disorders including myotonic dystrophy type I, spinal muscular atrophy and amyotrophic lateral sclerosis. Therefore, it is necessary to examine the impact of RNA-binding proteins during skeletal muscle development and plasticity in order to understand the consequences linked to their misregulation in disease. Here, we focused on the RNA-binding protein Staufen1, which assumes multiple roles in both skeletal muscle and neurons. We previously demonstrated that Staufen1 is regulated during myogenic differentiation and that its expression is increased in denervated and in myotonic dystrophy type I skeletal muscles. The increased expression of Staufen1 initially appeared beneficial for DM1 since further elevating Staufen1 levels rescued key hallmarks of the disease. However, based on the multi-functional nature of Staufen1, we hypothesized that Staufen1 acts as a disease modifier in DM1. To test this, we investigated the roles of Staufen1 in skeletal muscle biology and their implications for disease. Our data demonstrated that Staufen1 is required during the early stages of muscle development, however its expression must remain low in postnatal skeletal muscle. Interestingly, the overexpression of Staufen1 impaired myogenesis through the regulation of c-myc translation. Since the function of c-myc in oncogenesis is well described, we investigated the role of Staufen1 in cancer biology. In particular, we determined novel functions of Staufen1 in rhabdomyosarcoma tumorigenesis, thus providing the first direct evidence for Staufen1's involvement in cancer. Moreover, based on Staufen1's role in myogenic differentiation and in myotonic dystrophy type I, we generated muscle-specific transgenic mice to examine the impact of sustained Staufen1 expression in postnatal skeletal muscle. Staufen1 transgenic mice developed a myopathy characterized by histological and functional abnormalities via atrogene induction and the regulation of PTEN mRNAs. In parallel, we further investigated Staufen1-regulated alternative splicing and our data demonstrated that Staufen1 regulates multiple alternative splicing events in normal and myotonic dystrophy type I skeletal muscles, both beneficial and detrimental for the pathology. Collectively, these findings uncover several novel functions of Staufen1 in skeletal muscle biology and highlight Staufen1's role as a disease modifier in DM1.
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: Stefan Jurga
Publisher: Springer Nature
ISBN: 303044743X
Category : Medical
Languages : en
Pages : 545
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Book Description
This book offers a comprehensive and detailed overview of various aspects of long non-coding RNAs. It discusses their emerging significance in molecular medicine, ranging from human cancers to cardiovascular and metabolic diseases. Transcriptomic studies have demonstrated that the majority of genomes found in complex organisms are expressed in highly dynamic and cell-specific patterns, producing huge numbers of intergenic, antisense and intronic long non-protein-coding RNAs (lncRNAs). Thousands of lncRNAs have been identified, and unlike mRNA, they have no protein-coding capacity. A large repertoire of ncRNAs, actively transcribed from the mammalian genome, control diverse cellular processes, both in terms of development and diseases, through a variety of gene regulatory mechanisms. IncRNAs have emerged as a new paradigm in epigenetic regulation of the genome. Given its scope, the book will be of particular interest to molecular, chemical, cell and developmental biologists, as well as specialists in translational medicine involved in disease-oriented research. It also offers a valuable resource for in silico experts seeking a deeper understanding of lncRNA expression and function through computational analysis of the NGS data.
Author: Rita Sattler
Publisher: Springer
ISBN: 331989689X
Category : Medical
Languages : en
Pages : 321
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Book Description
It has become evident over the last years that abnormalities in RNA processing play a fundamental part in the pathogenesis of neurodegenerative diseases. Cellular viability depends on proper regulation of RNA metabolism and subsequent protein synthesis, which requires the interplay of many processes including transcription, pre--‐mRNA splicing, mRNA editing as well as mRNA stability, transport and translation. Dysfunction in any of these processes, often caused by mutations in the coding and non--‐ coding RNAs, can be very destructive to the cellular environment and consequently impair neural viability. The result of this RNA toxicity can lead to a toxic gain of function or a loss of function, depending on the nature of the mutation. For example, in repeat expansion disorders, such as the newly discovered hexanucleotide repeat expansion in theC9orf72 gene found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a toxic gain of function leads to the formation of RNA foci and the sequestration of RNA binding proteins (RBPs). This in return leads to a loss of function of those RBPs, which is hypothesized to play a significant part in the disease progression of ALS and FTD. Other toxicities arising from repeat expansions are the formation of RNA foci, bi--‐directional transcription and production of repeat associated non--‐ATG (RAN) translation products. This book will touch upon most of these disease mechanisms triggered by aberrant RNA metabolism and will therefore provide a broad perspective of the role of RNA processing and its dysfunction in a variety of neurodegenerative disorders, including ALS, FTD, Alzheimer’s disease, Huntington’s disease, spinal muscular atrophy, myotonic dystrophy and ataxias. The proposed authors are leading scientists in the field and are expected to not only discuss their own work, but to be inclusive of historic as well as late breaking discoveries. The compiled chapters will therefore provide a unique collection of novel studies and hypotheses aimed to describe the consequences of altered RNA processing events and its newest molecular players and pathways.
Author: Mansi Arora
Publisher: Springer
ISBN: 981131568X
Category : Medical
Languages : en
Pages : 323
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Book Description
In the last decade, researchers working in the field of cancer biology have shifted their focus from genetic defects to epigenetic dysregulation, especially that of non-coding RNAs (ncRNAs). This book encompasses a comprehensive review of the transcriptional landscape of the cell and its involvement in the cancer pathophysiology. The first two chapters elucidate the basics of biosynthesis, mechanism of action and modulation of the epigenetic regulation of gene expression by coding as well as non-coding RNAs. The third chapter discusses the aberrant expression of the cellular RNome in the cancer cells and highlights its role in the orchestration of processes involved in evolution as well as the sustenance of cancer cells. The fourth chapter describes the recent advances in the field of translating the transcriptome into diagnostic/prognostic biomarkers and as targets for novel anti-cancer therapies. The final chapter then reviews the emerging experimental approaches to screen, identify and explore the functions of ncRNAs. Providing valuable insights into the field of RNome in the context of cancer, this book is helpful to students, researchers and clinicians..
Author:
Publisher: Academic Press
ISBN: 0128171944
Category : Medical
Languages : en
Pages : 444
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Book Description
RNA-based Regulation in Human Health and Disease offers an in-depth exploration of RNA mediated genome regulation at different hierarchies. Beginning with multitude of canonical and non-canonical RNA populations, especially noncoding RNA in human physiology and evolution, further sections examine the various classes of RNAs (from small to large noncoding and extracellular RNAs), functional categories of RNA regulation (RNA-binding proteins, alternative splicing, RNA editing, antisense transcripts and RNA G-quadruplexes), dynamic aspects of RNA regulation modulating physiological homeostasis (aging), role of RNA beyond humans, tools and technologies for RNA research (wet lab and computational) and future prospects for RNA-based diagnostics and therapeutics. One of the core strengths of the book includes spectrum of disease-specific chapters from experts in the field highlighting RNA-based regulation in metabolic & neurodegenerative disorders, cancer, inflammatory disease, viral and bacterial infections. We hope the book helps researchers, students and clinicians appreciate the role of RNA-based regulation in genome regulation, aiding the development of useful biomarkers for prognosis, diagnosis, and novel RNA-based therapeutics. Comprehensive information of non-canonical RNA-based genome regulation modulating human health and disease Defines RNA classes with special emphasis on unexplored world of noncoding RNA at different hierarchies Disease specific role of RNA - causal, prognostic, diagnostic and therapeutic Features contributions from leading experts in the field
Author: Jeanette Erdmann
Publisher: Springer Nature
ISBN: 3030273717
Category : Medical
Languages : en
Pages : 407
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Book Description
This book provides a comprehensive summary of the latest developments in the field of the genomics of cardiac disease. Written and edited by leading clinicians and scientists involved in the analysis and therapy of genetic cardiac disorders, it discusses the genetic causes of a variety of cardiac diseases, such as the complex genetics and etiology of congenital heart diseases. It also explores sex differences in prevalent diseases, genetics-based therapeutic strategies and the use of various animal models and alternatives. The book is intended for research scientists and clinical scientists in the cardiovascular field, human geneticists and cardiologists.
Author: Tapas Kumar Kundu
Publisher: Springer Science & Business Media
ISBN: 9400745257
Category : Medical
Languages : en
Pages : 698
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Book Description
Epigenetics fine-tunes the life processes dictated by DNA sequences, but also kick-starts pathophysiological processes including diabetes, AIDS and cancer. This volume tracks the latest research on epigenetics, including work on new-generation therapeutics.
