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Berlin Brandenburg

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  • 1
    Book
    Book
    Springer International Publishing, Cham
    Language: English
    Description: Intro -- Parts of this thesis have been published in the following articles: -- Supervisor's Foreword -- Acknowledgments -- Contents -- Author's Biography -- Abbreviations -- 1 Introduction -- 1.1 The Life Cycle of an Eukaryotic mRNA Molecule -- 1.2 RNA-Binding Proteins -- 1.3 RNA-Binding Proteins and Disease -- 1.4 The RNA-Binding Protein LIN28 -- 1.4.1 Lin28 Inhibits miRNA Let-7 Biogenesis -- 1.4.2 Mechanism of Lin28-Let-7 Recognition -- 1.4.3 The Functional Role of Lin28 in Stem Cell Biology, Cancer and Metabolism -- 1.4.4 Lin28 Can Function Independent of Let-7 -- 1.4.5 Lin28 as a Direct Regulator of mRNA Translation -- 1.5 MicroRNAs -- 1.6 Cis-regulatory Sequence Elements in Eukaryotes -- 1.6.1 Upstream Open Reading Frames (uORFs) -- 1.6.2 Internal Ribosome Entry Sites (IRESs) -- 1.6.3 Ribosome Frameshift Signals (RFSs) -- 1.6.4 Splicing Regulatory Elements (SREs) -- 1.6.5 Iron Response Elements (IREs) -- 1.6.6 RNA Methylation Sites -- 1.6.7 AU-Rich Elements (AREs) -- 1.6.8 Zipcodes -- 1.6.9 Polyadenylation Signals (PASs) -- 1.7 Target Site Identification of Post-transcriptional Regulators -- 1.7.1 From the Study of a Single RBP to the `Post-transcriptional Regulatome' -- References -- 2 Mapping Regulatory Interactions of the RNA-Binding Protein LIN28B -- 2.1 PAR-CLIP Reproducibly Identifies Thousands of Human RNAs Directly Bound by LIN28B -- 2.2 LIN28B Binds to Let-7 Precursors and Protein Coding Transcripts -- 2.3 Target Transcripts Are Enriched for a RGGSWG Consensus Motif -- 2.4 Individual Domain PAR-CLIP Enables Characterization of Domain Specific Target Interactions -- 2.5 LIN28B Enhances Protein Production of mRNA Target Transcripts -- 2.6 LIN28B Controls Core Cell Cycle Regulators -- References -- 3 Exploring the Sequence Space Contacted by the Ensemble of RNA-Binding Proteins -- 3.1 Protein Occupancy Profiling Provides Catalog of Protein-mRNA Contact Sites -- 3.2 Protein Occupancy Profiling Recapitulates AGO Binding Pattern at miRNA Target Sites -- 3.3 Protein Occupancy Profiling Reveals Widespread and Conserved Protein-mRNA Contacts -- 3.4 Putative RNA Cis-regulatory Elements Overlap with Trait/Disease-Associated Polymorphisms -- 3.5 The Impact of Actively Translating Ribosomes on Protein Occupancy Profiles -- References -- 4 Revealing Cell-Type Specific Differences in Protein Occupancy on RNA -- 4.1 Protein Occupancy Profiling in MCF7 Cells -- 4.2 Comparing Gene Expression and Protein Occupancy Profiles in MCF7 and HEK293 Cells -- 4.3 Differential Protein Occupancy Profiling Based on T-C Transitions -- 4.4 Identification of Differentially Occupied RNA Regions Between MCF7 and HEK293 Cells -- 4.5 Differentially Occupied Positions Show Distinct Secondary-Structure Characteristics and Overlap with Binding Sites of Known RBPs -- 4.6 Transcripts with Increased Protein Occupancy in MCF7 Cells Show Elevated mRNA Half-Lives -- References -- 5 Discussion -- 5.1 PAR-CLIP and iDo-PAR-CLIP: Challenges and Considerations -- 5.1.1 PAR-CLIP Depends on Effective Metabolic Labeling of RNA -- 5.1.2 Potential Biases in CLIP and PAR-CLIP Experiments -- 5.1.3 Individual Domain PAR-CLIP: Asymmetry Is Key -- 5.2 Controlling Background in CLIP and PAR-CLIP Experiments -- 5.2.1 The Advantage of Combining Old and New Ways to Capturing RNA Targets -- 5.2.2 The Challenge of the Next Generation: Controlling Sequencing Depth -- 5.3 Transcriptome-Wide Identification of LIN28B-Bound RNA Targets -- 5.3.1 Multiple Studies Identify Lin28A and Lin28B-Bound RNA Targets in Different Systems -- 5.3.2 From Transcriptome-Wide Lin28 Binding Sites to a Model of mRNA Recognition -- 5.3.3 A Direct Role for LIN28B in Regulating Protein Synthesis -- 5.4 The Emerging Picture: Protein Production Is Regulated by Lin28 Through Let-7-Dependent and Let-7-Independent Mechanisms -- 5.4.1 Let-7-Dependent Effects of Lin28 -- 5.4.2 Let-7-Independent Effects of Lin28 -- 5.4.3 Merging Two Worlds: MRNA Translation Is Directly Regulated by Lin28 and Let-7 -- 5.5 Transcriptome-Wide Protein Occupancy Profiling -- 5.5.1 Protein Occupancy Profiling and the mRNA Bound Proteome -- 5.5.2 Characteristics of Protein Occupancy Profiles -- 5.5.3 Protein Occupancy and mRNA-Expression: A Distant Relationship? -- 5.5.4 Protein Occupancy and Ribosomes: An Unexpected Crosslinking Bias -- 5.5.5 Differential Protein Occupancy: From Crosslinks to Regulators -- 5.5.6 Transcriptome-Wide and Unbiased Identification of Novel Cis-acting RNA Elements -- 5.5.7 Lessons from the RBP-Bound mRNA Sequence Space -- 5.5.8 Application of Protein Occupancy Profiling and Future Directions -- References -- Supplementary Information -- .
    Keywords: Engineering -- Biomedical Engineering; Engineering -- Systems Biology; Engineering -- Computational Biology/Bioinformatics
    ISBN: 978-3-319-16252-2
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  • 2
    In: EMBO Journal, 02 July 2018, Vol.37(13), pp.n/a-n/a
    Description: Long non‐coding s (lncs) play important roles in many cellular pathways, but their contribution to the defense of eukaryotic cells against pathogens remains poorly understood. A new study from Imamura in reports that infection in human cells impacts nuclear decay, which in turn drives the accumulation of otherwise unstable nuclear lncs, some of which may have protective effects against this common bacterial pathogen. These unexpected findings demand more efforts to fully decrypt the molecular functions of lncs in innate and adaptive immunity. infection impairs the nuclear RNA decay machinery in human cells, increasing the abundance of long non‐coding RNAs with a role in innate immunity.
    Keywords: Pathogens ; Immunity ; Infections ; Pathogens ; Molecular Chains ; Salmonella ; Bacterial Infections ; Pathogens ; Ribonucleic Acid–RNA ; Ribonucleic Acid–RNA ; Adaptive Immunity;
    ISSN: 0261-4189
    E-ISSN: 1460-2075
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  • 3
    Language: English
    In: Nature, September 2018, Vol.561(7721), pp.132-136
    Description: The human genome contains thousands of long non-coding RNAs, but specific biological functions and biochemical mechanisms have been discovered for only about a dozen. A specific long non-coding RNA-non-coding RNA activated by DNA damage (NORAD)-has recently been shown to be required for maintaining genomic stability, but its molecular mechanism is unknown. Here we combine RNA antisense purification and quantitative mass spectrometry to identify proteins that directly interact with NORAD in living cells. We show that NORAD interacts with proteins involved in DNA replication and repair in steady-state cells and localizes to the nucleus upon stimulation with replication stress or DNA damage. In particular, NORAD interacts with RBMX, a component of the DNA-damage response, and contains the strongest RBMX-binding site in the transcriptome. We demonstrate that NORAD controls the ability of RBMX to assemble a ribonucleoprotein complex-which we term NORAD-activated ribonucleoprotein complex 1 (NARC1)-that contains the known suppressors of genomic instability topoisomerase I (TOP1), ALYREF and the PRPF19-CDC5L complex. Cells depleted for NORAD or RBMX display an increased frequency of chromosome segregation defects, reduced replication-fork velocity and altered cell-cycle progression-which represent phenotypes that are mechanistically linked to TOP1 and PRPF19-CDC5L function. Expression of NORAD in trans can rescue defects caused by NORAD depletion, but rescue is significantly impaired when the RBMX-binding site in NORAD is deleted. Our results demonstrate that the interaction between NORAD and RBMX is important for NORAD function, and that NORAD is required for the assembly of the previously unknown topoisomerase complex NARC1, which contributes to maintaining genomic stability. In addition, we uncover a previously unknown function for long non-coding RNAs in modulating the ability of an RNA-binding protein to assemble a higher-order ribonucleoprotein complex.
    Keywords: Genomic Instability ; DNA Topoisomerases, Type I -- Metabolism ; Multiprotein Complexes -- Chemistry ; RNA, Long Noncoding -- Metabolism ; RNA-Binding Proteins -- Metabolism
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 4
    Language: English
    In: Nature, November 2018, Vol.563(7733), pp.E32
    Description: A typo in the 'Reviewer information' section of this Letter was corrected online.
    Keywords: Genomics;
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 5
    In: Nature, 2012, Vol.492(7429), p.382
    Description: Fragile X syndrome (FXS) is a multi-organ disease that leads to mental retardation, macro-orchidism in males and premature ovarian insufficiency in female carriers. FXS is also a prominent monogenic disease associated with autism spectrum disorders (ASDs). FXS is typically caused by the loss of fragile X mental retardation 1 (FMR1) expression, which codes for the RNA-binding protein FMRP. Here we report the discovery of distinct RNA-recognition elements that correspond to the two independent RNA-binding domains of FMRP, in addition to the binding sites within the messenger RNA targets for wild-type and I304N mutant FMRP isoforms and the FMRP paralogues FXR1P and FXR2P (also known as FXR1 and FXR2). RNA-recognition-element frequency, ratio and distribution determine target mRNA association with FMRP.Among highly enriched targets,we identify many genes involved in ASD and show that FMRP affects their protein levels in human cell culture, mouse ovaries and human brain. Notably, we discovered that these targets are also dysregulated in Fmr1^sup -/-^ mouse ovaries showing signs of premature follicular overdevelopment. These results indicate that FMRP targets share signalling pathways across different cellular contexts. As the importance of signalling pathways in both FXS and ASD is becoming increasingly apparent, our results provide a ranked list of genes as basis for the pursuit of new therapeutic targets for these neurological disorders. [PUBLICATION ]
    Keywords: Animals–Metabolism ; Base Sequence–Genetics ; Binding Sites–Metabolism ; Brain–Genetics ; Child–Metabolism ; Child Development Disorders, Pervasive–Genetics ; Child Development Disorders, Pervasive–Metabolism ; Cross-Linking Reagents–Pathology ; Female–Genetics ; Fragile X Mental Retardation Protein–Genetics ; Fragile X Mental Retardation Protein–Metabolism ; Gene Expression Regulation–Genetics ; Hek293 Cells–Genetics ; Humans–Genetics ; Immunoprecipitation–Genetics ; Mice–Genetics ; Molecular Sequence Data–Genetics ; Multigene Family–Genetics ; Mutation–Genetics ; Ovary–Genetics ; Ovary–Genetics ; Protein Biosynthesis–Genetics ; RNA, Messenger–Genetics ; RNA, Messenger–Genetics ; Regulatory Sequences, Ribonucleic Acid–Genetics ; Response Elements–Genetics ; Signal Transduction–Genetics ; Substrate Specificity–Genetics ; Binding Sites ; Proteins ; Gene Expression ; Protein Synthesis ; Cell Culture ; Methods ; Cross-Linking Reagents ; Fmr1 Protein, Human ; Fmr1 Protein, Mouse ; RNA, Messenger ; Regulatory Sequences, Ribonucleic Acid ; Fragile X Mental Retardation Protein;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 6
    In: Nature, 2013, Vol.495(7441), p.333
    Description: Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences. [PUBLICATION ]
    Keywords: Animals–Genetics ; Autoantigens–Metabolism ; Autoantigens–Metabolism ; Binding Sites–Genetics ; Brain–Metabolism ; Caenorhabditis Elegans–Genetics ; Caenorhabditis Elegans–Metabolism ; Cell Line–Genetics ; Conserved Sequence–Metabolism ; Female–Genetics ; Gene Expression Regulation–Metabolism ; Hek293 Cells–Embryology ; Humans–Genetics ; Male–Metabolism ; Mice–Metabolism ; Micrornas–Metabolism ; Micrornas–Metabolism ; Nerve Tissue Proteins–Metabolism ; Nerve Tissue Proteins–Metabolism ; RNA–Metabolism ; RNA–Metabolism ; Zebrafish–Metabolism ; Zebrafish–Metabolism ; Zebrafish–Metabolism ; Ribonucleic Acid–RNA ; Proteins ; Zebrafish ; Seeds ; Cell Culture ; Genomes ; Competition ; Stem Cells ; Methods ; RNA Polymerase ; Autoantigens ; Cdr1 Protein, Human ; Mirn7 Microrna, Human ; Micrornas ; Nerve Tissue Proteins ; RNA, Circular ; RNA;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 7
    Language: English
    In: Methods, February 2014, Vol.65(3), pp.302-309
    Description: A key prerequisite to understand how gene regulatory processes are controlled by the interplay of RNA-binding proteins and ribonucleoprotein complexes with RNAs is the generation of comprehensive high-resolution maps of protein–RNA interactions. Recent advances in next-generation sequencing technology accelerated the development of various crosslinking and immunoprecipitation (CLIP) approaches to broadly identify RNA regions contacted by RNA-binding proteins. However these methods only consider single RNA-binding proteins and their contact sites, irrespective of the overall -regulatory sequence space contacted by other RNA interacting factors. Here we describe the application of protein occupancy profiling, a novel approach that globally displays the RNA contact sites of the poly(A)+ RNA-bound proteome. Protein occupancy profiling enables the generation of transcriptome-wide maps of protein–RNA interactions on polyadenylated transcripts and narrows the sequence search space for transcript regions involved in -regulation of gene expression in response to internal or external stimuli, altered cellular programs or disease.
    Keywords: Clip ; Par-Clip ; Mrna ; Lincrna ; Protein Occupancy Profiling ; Non-Coding RNA ; Protein–RNA Interaction ; RNA-Binding Protein ; Next-Generation Sequencing ; Chemistry ; Anatomy & Physiology
    ISSN: 1046-2023
    E-ISSN: 1095-9130
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  • 8
    Language: English
    In: Science (New York, N.Y.), 11 November 2016, Vol.354(6313), pp.769-773
    Description: Gene expression in mammals is regulated by noncoding elements that can affect physiology and disease, yet the functions and target genes of most noncoding elements remain unknown. We present a high-throughput approach that uses clustered regularly interspaced short palindromic repeats (CRISPR) interference (CRISPRi) to discover regulatory elements and identify their target genes. We assess 〉1 megabase of sequence in the vicinity of two essential transcription factors, MYC and GATA1, and identify nine distal enhancers that control gene expression and cellular proliferation. Quantitative features of chromatin state and chromosome conformation distinguish the seven enhancers that regulate MYC from other elements that do not, suggesting a strategy for predicting enhancer-promoter connectivity. This CRISPRi-based approach can be applied to dissect transcriptional networks and interpret the contributions of noncoding genetic variation to human disease.
    Keywords: Clustered Regularly Interspaced Short Palindromic Repeats ; Chromosome Mapping -- Methods ; Enhancer Elements, Genetic -- Physiology ; High-Throughput Nucleotide Sequencing -- Methods ; Promoter Regions, Genetic -- Physiology
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 9
    Language: English
    In: Cell, 2010, Vol.141(1), pp.129-141
    Description: RNA transcripts are subject to posttranscriptional gene regulation involving hundreds of RNA-binding proteins (RBPs) and microRNA-containing ribonucleoprotein complexes (miRNPs) expressed in a cell-type dependent fashion. We developed a cell-based crosslinking approach to determine at high resolution and transcriptome-wide the binding sites of cellular RBPs and miRNPs. The crosslinked sites are revealed by thymidine to cytidine transitions in the cDNAs prepared from immunopurified RNPs of 4-thiouridine-treated cells. We determined the binding sites and regulatory consequences for several intensely studied RBPs and miRNPs, including PUM2, QKI, IGF2BP1-3, AGO/EIF2C1-4 and TNRC6A-C. Our study revealed that these factors bind thousands of sites containing defined sequence motifs and have distinct preferences for exonic versus intronic or coding versus untranslated transcript regions. The precise mapping of binding sites across the transcriptome will be critical to the interpretation of the rapidly emerging data on genetic variation between individuals and how these variations contribute to complex genetic diseases. ► PAR-CLIP is a transcriptome-wide crosslinking method for RNA-binding proteins (RBP) ► It is based on incorporation of photoactivatable nucleoside analogs into nascent RNA ► Characteristic sequence transitions in the prepared cDNA reveal the precise binding site ► We deduced binding motifs and preferences for 5 different RBP families
    Keywords: RNA ; Proteins ; Sysbio ; Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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  • 10
    Language: English
    In: Genome biology, 13 January 2014, Vol.15(1), pp.R15
    Description: RNA-binding proteins (RBPs) mediate mRNA biogenesis, translation and decay. We recently developed an approach to profile transcriptome-wide RBP contacts on polyadenylated transcripts by next-generation sequencing. A comparison of such profiles from different biological conditions has the power to unravel dynamic changes in protein-contacted cis-regulatory mRNA regions without a priori knowledge of the regulatory protein component. We compared protein occupancy profiles of polyadenylated transcripts in MCF7 and HEK293 cells. Briefly, we developed a bioinformatics workflow to identify differential crosslinking sites in cDNA reads of 4-thiouridine crosslinked polyadenylated RNA samples. We identified 30,000 differential crosslinking sites between MCF7 and HEK293 cells at an estimated false discovery rate of 10%. 73% of all reported differential protein-RNA contact sites cannot be explained by local changes in exon usage as indicated by complementary RNA-seq data. The majority of differentially crosslinked positions are located in 3' UTRs, show distinct secondary-structure characteristics and overlap with binding sites of known RBPs, such as ELAVL1. Importantly, mRNA transcripts with the most significant occupancy changes show elongated mRNA half-lives in MCF7 cells. We present a global comparison of protein occupancy profiles from different cell types, and provide evidence for altered mRNA metabolism as a result of differential protein-RNA contacts. Additionally, we introduce POPPI, a bioinformatics workflow for the analysis of protein occupancy profiling experiments. Our work demonstrates the value of protein occupancy profiling for assessing cis-regulatory RNA sequence space and its dynamics in growth, development and disease.
    Keywords: Transcriptome ; RNA, Messenger -- Metabolism ; RNA-Binding Proteins -- Metabolism
    ISSN: 14656906
    E-ISSN: 1474-760X
    E-ISSN: 14656914
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