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  • 1
    Language: English
    In: Genome biology, 2018-03-28, Vol.19 (1), p.1-17
    Description: 3′ Untranslated regions (3' UTRs) length is regulated in relation to cellular state. To uncover key regulators of poly(A) site use in specific conditions, we have developed PAQR, a method for quantifying poly(A) site use from RNA sequencing data and KAPAC, an approach that infers activities of oligomeric sequence motifs on poly(A) site choice. Application of PAQR and KAPAC to RNA sequencing data from normal and tumor tissue samples uncovers motifs that can explain changes in cleavage and polyadenylation in specific cancers. In particular, our analysis points to polypyrimidine tract binding protein 1 as a regulator of poly(A) site choice in glioblastoma.
    Subject(s): Poly(A) ; Glioblastoma ; Data processing ; Genomes ; RNA polymerase ; Gene expression ; Ribonucleic acid--RNA ; Proteins ; Maps ; 3' Untranslated regions ; Polyadenylation ; Bioinformatics ; Binding sites ; Cancer ; CFIm ; Cleavage and polyadenylation ; APA ; KAPAC ; HNRNPC ; PAQR
    ISSN: 1474-760X
    ISSN: 1474-7596
    E-ISSN: 1474-760X
    Source: BioMedCentral
    Source: BioMedCentral Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: Genome biology, 2015-07-23, Vol.16 (1), p.150-150
    Description: Understanding the regulation of gene expression, including transcription start site usage, alternative splicing, and polyadenylation, requires accurate quantification of expression levels down to the level of individual transcript isoforms. To comparatively evaluate the accuracy of the many methods that have been proposed for estimating transcript isoform abundance from RNA sequencing data, we have used both synthetic data as well as an independent experimental method for quantifying the abundance of transcript ends at the genome-wide level. We found that many tools have good accuracy and yield better estimates of gene-level expression compared to commonly used count-based approaches, but they vary widely in memory and runtime requirements. Nucleotide composition and intron/exon structure have comparatively little influence on the accuracy of expression estimates, which correlates most strongly with transcript/gene expression levels. To facilitate the reproduction and further extension of our study, we provide datasets, source code, and an online analysis tool on a companion website, where developers can upload expression estimates obtained with their own tool to compare them to those inferred by the methods assessed here. As many methods for quantifying isoform abundance with comparable accuracy are available, a user's choice will likely be determined by factors such as the memory and runtime requirements, as well as the availability of methods for downstream analyses. Sequencing-based methods to quantify the abundance of specific transcript regions could complement validation schemes based on synthetic data and quantitative PCR in future or ongoing assessments of RNA-seq analysis methods.
    Subject(s): Sequence Analysis, RNA - methods ; NIH 3T3 Cells ; Animals ; Jurkat Cells ; Humans ; RNA Isoforms - analysis ; Gene Expression Profiling - methods ; Mice ; Software ; High-Throughput Nucleotide Sequencing - methods ; Alternative splicing ; Transcription ; Abundance ; Genomes ; Mammals ; Gene expression ; Ribonucleic acid--RNA ; Proteins ; Accuracy ; Algorithms ; Archives & records ; Polyadenylation ; Isoforms ; Computer applications ; Bioinformatics ; Research
    ISSN: 1465-6906
    ISSN: 1474-7596
    E-ISSN: 1474-760X
    E-ISSN: 1465-6914
    Source: BioMedCentral
    Source: BioMedCentral Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 3
    Language: English
    In: Genome biology, 2018-03-28, Vol.19 (1), p.44-44
    Description: 3' Untranslated regions (3' UTRs) length is regulated in relation to cellular state. To uncover key regulators of poly(A) site use in specific conditions, we have developed PAQR, a method for quantifying poly(A) site use from RNA sequencing data and KAPAC, an approach that infers activities of oligomeric sequence motifs on poly(A) site choice. Application of PAQR and KAPAC to RNA sequencing data from normal and tumor tissue samples uncovers motifs that can explain changes in cleavage and polyadenylation in specific cancers. In particular, our analysis points to polypyrimidine tract binding protein 1 as a regulator of poly(A) site choice in glioblastoma.
    Subject(s): PTBP1 ; APA ; KAPAC ; Colon adenocarcinoma ; PAQR ; Glioblastoma ; CFIm ; Cleavage and polyadenylation ; Method ; HNRNPC ; Prostate adenocarcinoma
    ISSN: 1474-7596
    E-ISSN: 1474-760X
    Source: BioMedCentral
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 4
    Language: English
    In: Cell reports (Cambridge), 2012-06-28, Vol.1 (6), p.753-763
    Description: Through alternative polyadenylation, human mRNAs acquire longer or shorter 3′ untranslated regions, the latter typically associated with higher transcript stability and increased protein production. To understand the dynamics of polyadenylation site usage, we performed transcriptome-wide mapping of both binding sites of 3′ end processing factors CPSF-160, CPSF-100, CPSF-73, CPSF-30, Fip1, CstF-64, CstF-64τ, CF Im25, CF Im59, and CF Im68 and 3′ end processing sites in HEK293 cells. We found that although binding sites of these factors generally cluster around the poly(A) sites most frequently used in cleavage, CstF-64/CstF-64τ and CFIm proteins have much higher positional specificity compared to CPSF components. Knockdown of CF Im68 induced a systematic use of proximal polyadenylation sites, indicating that changes in relative abundance of a single 3′ end processing factor can modulate the length of 3′ untranslated regions across the transcriptome and suggesting a mechanism behind the previously observed increase in tumor cell invasiveness upon CF Im68 knockdown. [Display omitted] ► Thousands of poly(A) sites are identified by the A-seq method in a human cell line ► Binding sites of pre-mRNA 3′ end processing factors are mapped by PAR-CLIP ► CstF-64 and CF Im68 exhibit the highest positional binding specificity ► CF Im 68 siRNA treatment causes a global shift toward proximal poly(A) sites Alternative cleavage and polyadenylation generate mRNAs with 3′ untranslated regions of different lengths. Keller, Zavolan, and colleagues mapped the binding sites of ten 3′ end processing proteins by PAR-CLIP and identified the 3′ end processing sites by A-seq. CstF-64 and CF Im68 proteins showed the highest positional specificity. Knockdown of CF Im68 induced a systematic shift toward proximal polyadenylation sites, indicating that changes in the relative abundance of a single 3′ end processing factor can modulate the length of 3′ untranslated regions transcriptome-wide.
    Subject(s): Protein Binding - genetics ; Cell Proliferation ; Nucleotide Motifs - genetics ; mRNA Cleavage and Polyadenylation Factors - metabolism ; Humans ; Genetic Loci - genetics ; 3' Untranslated Regions - genetics ; Molecular Sequence Data ; RNA Precursors - genetics ; Genome, Human - genetics ; Gene Knockdown Techniques ; Blotting, Northern ; Poly A - metabolism ; Polyadenylation - genetics ; Models, Biological ; Base Sequence ; HEK293 Cells ; RNA Precursors - metabolism ; RNA 3' End Processing - genetics ; Binding Sites ; RNA-Binding Proteins - metabolism
    ISSN: 2211-1247
    E-ISSN: 2211-1247
    Source: Alma/SFX Local Collection
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 5
    Language: English
    In: Nature reviews. Genetics, 2019-10-01, Vol.20 (10), p.599-614
    Description: Most human genes have multiple sites at which RNA 3. end cleavage and polyadenylation can occur, enabling the expression of distinct transcript isoforms under different conditions. Novel methods to sequence RNA 3' ends have generated comprehensive catalogues of polyadenylation (poly(A)) sites; their analysis using innovative computational methods has revealed how poly(A) site choice is regulated by core RNA 3. end processing factors, such as cleavage factor I and cleavage and polyadenylation specificity factor, as well as by other RNA-binding proteins, particularly splicing factors. Here, we review the experimental and computational methods that have enabled the global mapping of mRNA and of long non-coding RNA 3. ends, quantification of the resulting isoforms and the discovery of regulators of alternative cleavage and polyadenylation (APA). We highlight the different types of APA-derived isoforms and their functional differences, and illustrate how APA contributes to human diseases, including cancer and haematological, immunological and neurological diseases.
    Subject(s): Life Sciences & Biomedicine ; Genetics & Heredity ; Science & Technology ; RNA-Binding Proteins - genetics ; Polyadenylation - genetics ; Animals ; Disease - genetics ; Health ; Humans ; RNA, Messenger - genetics ; 3' Untranslated Regions - genetics ; RNA, Long Noncoding - genetics
    ISSN: 1471-0056
    E-ISSN: 1471-0064
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: Nature Journals Online
    Source: Nature Reviews
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  • 6
    Language: English
    In: BMC bioinformatics, 2008-11-11, Vol.9 (1), p.474-474
    Description: The prediction of a consensus structure for a set of related RNAs is an important first step for subsequent analyses. RNAalifold, which computes the minimum energy structure that is simultaneously formed by a set of aligned sequences, is one of the oldest and most widely used tools for this task. In recent years, several alternative approaches have been advocated, pointing to several shortcomings of the original RNAalifold approach. We show that the accuracy of RNAalifold predictions can be improved substantially by introducing a different, more rational handling of alignment gaps, and by replacing the rather simplistic model of covariance scoring with more sophisticated RIBOSUM-like scoring matrices. These improvements are achieved without compromising the computational efficiency of the algorithm. We show here that the new version of RNAalifold not only outperforms the old one, but also several other tools recently developed, on different datasets. The new version of RNAalifold not only can replace the old one for almost any application but it is also competitive with other approaches including those based on SCFGs, maximum expected accuracy, or hierarchical nearest neighbor classifiers.
    Subject(s): Amino Acid Sequence ; Computational Biology - methods ; Sequence Alignment ; Algorithms ; Models, Chemical ; Software ; Nucleic Acid Conformation ; RNA - chemistry ; Proteins ; RNA ; Structure ; Protein folding ; Identification and classification ; Methodology
    ISSN: 1471-2105
    E-ISSN: 1471-2105
    Source: BioMedCentral Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 7
    Language: English
    In: Genome research, 2016-08, Vol.26 (8), p.1145-1159
    Description: Alternative polyadenylation (APA) is a general mechanism of transcript diversification in mammals, which has been recently linked to proliferative states and cancer. Different 3' untranslated region (3' UTR) isoforms interact with different RNA-binding proteins (RBPs), which modify the stability, translation, and subcellular localization of the corresponding transcripts. Although the heterogeneity of pre-mRNA 3' end processing has been established with high-throughput approaches, the mechanisms that underlie systematic changes in 3' UTR lengths remain to be characterized. Through a uniform analysis of a large number of 3' end sequencing data sets, we have uncovered 18 signals, six of which are novel, whose positioning with respect to pre-mRNA cleavage sites indicates a role in pre-mRNA 3' end processing in both mouse and human. With 3' end sequencing we have demonstrated that the heterogeneous ribonucleoprotein C (HNRNPC), which binds the poly(U) motif whose frequency also peaks in the vicinity of polyadenylation (poly(A)) sites, has a genome-wide effect on poly(A) site usage. HNRNPC-regulated 3' UTRs are enriched in ELAV-like RBP 1 (ELAVL1) binding sites and include those of the CD47 gene, which participate in the recently discovered mechanism of 3' UTR-dependent protein localization (UDPL). Our study thus establishes an up-to-date, high-confidence catalog of 3' end processing sites and poly(A) signals, and it uncovers an important role of HNRNPC in regulating 3' end processing. It further suggests that U-rich elements mediate interactions with multiple RBPs that regulate different stages in a transcript's life cycle.
    Subject(s): RNA-Binding Proteins - genetics ; Gene Expression ; Polyadenylation - genetics ; Animals ; Heterogeneous-Nuclear Ribonucleoprotein Group C - genetics ; Humans ; RNA, Messenger - genetics ; 3' Untranslated Regions - genetics ; Transcription, Genetic ; Cytoplasm - genetics ; Mice ; Binding Sites ; Resource
    ISSN: 1088-9051
    E-ISSN: 1549-5469
    Source: HighWire Press (Free Journals)
    Source: Hellenic Academic Libraries Link
    Source: Cold Spring Harbor Laboratory Press
    Source: PubMed Central
    Source: Alma/SFX Local Collection
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  • 8
    Language: English
    In: Nature communications, 2014-11-21, Vol.5 (1), p.5465-5465
    Description: Alternative polyadenylation is a cellular mechanism that generates mRNA isoforms differing in their 3' untranslated regions (3' UTRs). Changes in polyadenylation site usage have been described upon induction of proliferation in resting cells, but the underlying mechanism and functional significance of this phenomenon remain largely unknown. To understand the functional consequences of shortened 3' UTR isoforms in a physiological setting, we used 3' end sequencing and quantitative mass spectrometry to determine polyadenylation site usage, mRNA and protein levels in murine and human naive and activated T cells. Although 3' UTR shortening in proliferating cells is conserved between human and mouse, orthologous genes do not exhibit similar expression of alternative 3' UTR isoforms. We generally find that 3' UTR shortening is not accompanied by a corresponding change in mRNA and protein levels. This suggests that although 3' UTR shortening may lead to changes in the RNA-binding protein interactome, it has limited effects on protein output.
    Subject(s): Cell Line ; Cell Proliferation ; Humans ; Mice, Inbred C57BL ; RNA, Messenger - genetics ; Cells, Cultured ; RNA, Messenger - metabolism ; Proteins - genetics ; Animals ; Proteins - metabolism ; T-Lymphocytes - cytology ; T-Lymphocytes - metabolism ; Polyadenylation ; Female ; Mice ; 3' Untranslated Regions
    ISSN: 2041-1723
    E-ISSN: 2041-1723
    Source: Nature Open Access
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 9
    Language: English
    In: Trees (Berlin, West), 2010-06-25, Vol.24 (5), p.887-898
    Description: Within a dry inner Alpine valley in the Eastern Central Alps (750 m a.s.l., Tyrol, Austria) the influence of climate variables (precipitation, air humidity, temperature) and soil water content on intra-annual dynamics of tree-ring development was determined in Scots pine (Pinus sylvestris L.) at two sites differing in soil water availability (xeric and dry-mesic site). Radial stem development was continuously followed during 2007 and 2008 by band dendrometers and repeated micro-sampling of the developing tree rings of mature trees. Daily and seasonal fluctuations of the stem radius, which reached almost half of total annual increment, primarily reflected changes in tree water status and masked radial stem growth especially during drought periods in spring. However, temporal dynamics of intra-annual radial growth determined by both methods were found to be quite similar, when onset of radial growth in dendrometer traces was defined by the occurrence of first enlarging xylem cells. Radial increments during the growing period, which lasted from early April through early August showed statistically significant relationships with precipitation (Kendall τ = 0.234, p 〈 0.01, and τ = 0.184, p 〈 0.05, at the xeric and dry-mesic site, respectively) and relative air humidity (Pearson r = 0.290, p 〈 0.05, and r = 0.306, p 〈 0.05 at the xeric and dry-mesic site, respectively). Soil water content and air temperature had no influence on radial stem increment. Culmination of radial stem growth was detected at both study plots around mid-May, prior to occurrence of more favourable climatic conditions, i.e. an increase in precipitation during summer. We suggest that the early decrease in radial growth rate is due to a high belowground demand for carbohydrates to ensure adequate resource acquisition on the drought prone substrate.
    Subject(s): Dendroclimatology ; Soil moisture ; Droughts ; Rain and rainfall ; Humidity ; Dendrometer ; Drought ; Dry inner Alpine valley ; Pinus sylvestris ; Xylem cell analysis ; Radial growth
    ISSN: 0931-1890
    E-ISSN: 1432-2285
    Source: Alma/SFX Local Collection
    Source: ProQuest Central
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  • 10
    Language: English
    In: Genome biology, 2013-05-26, Vol.14 (5), p.R45-R45
    Description: In recent years, a variety of small RNAs derived from other RNAs with well-known functions such as tRNAs and snoRNAs, have been identified. The functional relevance of these RNAs is largely unknown. To gain insight into the complexity of snoRNA processing and the functional relevance of snoRNA-derived small RNAs, we sequence long and short RNAs, small RNAs that co-precipitate with the Argonaute 2 protein and RNA fragments obtained in photoreactive nucleotide-enhanced crosslinking and immunoprecipitation (PAR-CLIP) of core snoRNA-associated proteins. Analysis of these data sets reveals that many loci in the human genome reproducibly give rise to C/D box-like snoRNAs, whose expression and evolutionary conservation are typically less pronounced relative to the snoRNAs that are currently cataloged. We further find that virtually all C/D box snoRNAs are specifically processed inside the regions of terminal complementarity, retaining in the mature form only 4-5 nucleotides upstream of the C box and 2-5 nucleotides downstream of the D box. Sequencing of the total and Argonaute 2-associated populations of small RNAs reveals that despite their cellular abundance, C/D box-derived small RNAs are not efficiently incorporated into the Ago2 protein. We conclude that the human genome encodes a large number of snoRNAs that are processed along the canonical pathway and expressed at relatively low levels. Generation of snoRNA-derived processing products with alternative, particularly miRNA-like, functions appears to be uncommon.
    Subject(s): Argonaute Proteins - metabolism ; Immunoprecipitation ; Humans ; RNA, Small Nucleolar - analysis ; Models, Molecular ; Molecular Sequence Data ; Cross-Linking Reagents - metabolism ; Ribonucleoproteins, Small Nucleolar - analysis ; RNA, Small Nucleolar - metabolism ; Sequence Analysis, RNA ; HEK293 Cells ; HeLa Cells ; Genome, Human ; Research
    ISSN: 1465-6906
    E-ISSN: 1474-760X
    E-ISSN: 1465-6914
    Source: BioMedCentral
    Source: BioMedCentral Open Access
    Source: PubMed Central
    Source: Alma/SFX Local Collection
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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