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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 23 December 2014, Vol.111(51), pp.18309-14
    Description: Posttranscriptional RNA regulation is important in determining the plasticity of cellular phenotypes. However, mechanisms of how RNA binding proteins (RBPs) influence cellular behavior are poorly understood. We show here that the RBP embryonic lethal abnormal vision like 1 (ELAVL1, also know as HuR) regulates the alternative splicing of eukaryotic translation initiation factor 4E nuclear import factor 1 (Eif4enif1), which encodes an eukaryotic translation initiation factor 4E transporter (4E-T) protein and suppresses the expression of capped mRNAs. In the absence of ELAVL1, skipping of exon 11 of Eif4enif1 forms the stable, short isoform, 4E-Ts. This alternative splicing event results in the formation of RNA processing bodies (PBs), enhanced turnover of angiogenic mRNAs, and suppressed sprouting behavior of vascular endothelial cells. Further, endothelial-specific Elavl1 knockout mice exhibited reduced revascularization after hind limb ischemia and tumor angiogenesis in oncogene-induced mammary cancer, resulting in attenuated blood flow and tumor growth, respectively. ELAVL1-regulated alternative splicing of Eif4enif1 leading to enhanced formation of PB and mRNA turnover constitutes a novel posttranscriptional mechanism critical for pathological angiogenesis.
    Keywords: RNA Binding Protein ; Alternative Splicing ; Angiogenesis ; Eif4e Transporter ; Tumor Angiogenesis ; Alternative Splicing -- Physiology ; Elav Proteins -- Physiology ; Neovascularization, Physiologic -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    In: Nature, 2013, Vol.495(7439), p.98
    Description: Adult stem cells reside in specialized niches where they receive environmental cues to maintain tissue homeostasis. In mammals, the stem cell niche within hair follicles is home to epithelial hair follicle stem cells and melanocyte stem cells, which sustain cyclical bouts of hair regeneration and pigmentation. To generate pigmented hairs, synchrony is achieved such that upon initiation of a new hair cycle, stem cells of each type activate lineage commitment. Dissecting the inter-stem-cell crosstalk governing this intricate coordination has been difficult, because mutations affecting one lineage often affect the other. Here we identify transcription factor NFIB as an unanticipated coordinator of stem cell behaviour. Hair follicle stem-cell-specific conditional targeting of Nfib in mice uncouples stem cell synchrony. Remarkably, this happens not by perturbing hair cycle and follicle architecture, but rather by promoting melanocyte stem cell proliferation and differentiation. The early production of melanin is restricted to melanocyte stem cells at the niche base. Melanocyte stem cells more distant from the dermal papilla are unscathed, thereby preventing hair greying typical of melanocyte stem cell differentiation mutants. Furthermore, we pinpoint KIT-ligand as a dermal papilla signal promoting melanocyte stem cell differentiation. Additionally, through chromatin-immunoprecipitation with high-throughput-sequencing and transcriptional profiling, we identify endothelin 2 (Edn2) as an NFIB target aberrantly activated in NFIB-deficient hair follicle stem cells. Ectopically induced Edn2 recapitulates NFIB-deficient phenotypes in wild-type mice. Conversely, endothelin receptor antagonists and/or KIT blocking antibodies prevent precocious melanocyte stem cell differentiation in the NFIB-deficient niche. Our findings reveal how melanocyte and hair follicle stem cell behaviours maintain reliance upon cooperative factors within the niche, and how this can be uncoupled in injury, stress and disease states.
    Keywords: Sciences (General) ; Physics;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(5), p.e63056
    Description: Microsatellite instability (MSI) is characterized by the expansion or contraction of DNA repeat tracts as a consequence of DNA mismatch repair deficiency (MMRD). Accurate detection of MSI in cancer cells is important since MSI is associated with several cancer subtypes and can help inform therapeutic...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: Cancer Research, 07/15/2016, Vol.76(14 Supplement), pp.3916-3916
    Description: Over the past decade, significant strides have been made in the management and treatment of various diseases. Despite this progress, clinical attrition rates have continued to substantially rise. Clinical trials can fail for a variety of reasons, ranging from design issues to drug efficacy and safety problems. Drug-likeness approaches, as first proposed by Lipinski almost two decades ago, have become a key tool for the pre-selection of compounds that are likely to have manageable toxicity in clinical studies. However all these methods consider molecular properties of the drug itself alone. In general, these approaches struggle to simultaneously well-characterize the properties of both FDA approved drugs (which we term the sensitivity) and drugs that fail clinical trials (specificity).
    Keywords: Drug Development ; Toxicity ; Drugs ; Clinical Trials ; Pharmaceuticals;
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 5
    Language: English
    In: Cancer Research, 07/01/2018, Vol.78(13 Supplement), pp.3896-3896
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 6
    Language: English
    In: Cancer Research, 07/01/2018, Vol.78(13 Supplement), pp.2225-2225
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 7
    In: PLoS ONE, 2010, Vol.5(12)
    Description: The increasing ability to generate large-scale, quantitative proteomic data has brought with it the challenge of analyzing such data to discover the sequence elements that underlie systems-level protein behavior. Here we show that short, linear protein motifs can be efficiently recovered from proteome-scale datasets such as sub-cellular localization, molecular function, half-life, and protein abundance data using an information theoretic approach. Using this approach, we have identified many known protein motifs, such as phosphorylation sites and localization signals, and discovered a large number of candidate elements. We estimate that ∼80% of these are novel predictions in that they do not match a known motif in both sequence and biological context, suggesting that post-translational regulation of protein behavior is still largely unexplored. These predicted motifs, many of which display preferential association with specific biological pathways and non-random positioning in the linear protein sequence, provide focused hypotheses for experimental validation.
    Keywords: Research Article ; Biotechnology ; Cell Biology/Membranes And Sorting ; Computational Biology/Genomics ; Computational Biology/Sequence Motif Analysis ; Genetics And Genomics/Bioinformatics ; Molecular Biology/Post-Translational Regulation Of Gene Expression
    E-ISSN: 1932-6203
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  • 8
    In: Nature, 2013, Vol.500(7460), p.89
    ISSN: 0028-0836
    E-ISSN: 1476-4687
    Source: Nature Publishing Group
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  • 9
    Language: English
    In: Cell, 22 June 2012, Vol.149(7), pp.1635-1646
    Description: Methylation of the position of adenosine (m A) is a posttranscriptional modification of RNA with poorly understood prevalence and physiological relevance. The recent discovery that FTO, an obesity risk gene, encodes an m A demethylase implicates m A as an important regulator of physiological processes. Here, we present a method for transcriptome-wide m A localization, which combines m A-specific methylated RNA immunoprecipitation with next-generation sequencing (MeRIP-Seq). We use this method to identify mRNAs of 7,676 mammalian genes that contain m A, indicating that m A is a common base modification of mRNA. The m A modification exhibits tissue-specific regulation and is markedly increased throughout brain development. We find that m A sites are enriched near stop codons and in 3′ UTRs, and we uncover an association between m A residues and microRNA-binding sites within 3′ UTRs. These findings provide a resource for identifying transcripts that are substrates for adenosine methylation and reveal insights into the epigenetic regulation of the mammalian transcriptome. ► m A is a widespread RNA modification in many tissues with high levels in the brain ► MeRIP-Seq identifies m A in 7,913 genes encoding both coding and noncoding RNAs ► m A is enriched near stop codons and within 3′ UTRs in both mouse and human mRNAs ► The transcriptome-wide landscape of m A provides important insights into m A function Adenosine methylation (m A) is a widespread RNA modification found in 〉7,000 mammalian genes, encoding both mRNAs and noncoding RNAs, with an especially high prevalence in the developing brain. In both mouse and human mRNAs, m A is enriched within 3′ UTRs that also contain miRNA-binding sites.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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  • 10
    Language: English
    In: Nature, 02 November 2017, Vol.551(7678), pp.95-99
    Description: Pathogens have to balance transmission with persistence. For Plasmodium falciparum, the most widespread and virulent malaria parasite, persistence within its human host requires continuous asexual replication within red blood cells, while its mosquito-borne transmission depends on intra-erythrocytic differentiation into non-replicating sexual stages called gametocytes. Commitment to either fate is determined during the preceding cell cycle that begins with invasion by a single, asexually committed merozoite and ends, 48 hours later, with a schizont releasing newly formed merozoites, all committed to either continued asexual replication or differentiation into gametocytes. Sexual commitment requires the transcriptional activation of ap2-g (PF3D7_1222600), the master regulator of sexual development, from an epigenetically silenced state during asexual replication. AP2-G expression during this 'commitment cycle' prepares gene expression in nascent merozoites to initiate sexual development through a hitherto unknown mechanism. To maintain a persistent infection, the expression of ap2-g is limited to a sub-population of parasites (1-30%, depending on genetic background and growth conditions). As sexually committed schizonts comprise only a sub-population and are morphologically indistinguishable from their asexually committed counterparts, defining their characteristic gene expression has been difficult using traditional, bulk transcriptome profiling. Here we use highly parallel, single-cell RNA sequencing of malaria cultures undergoing sexual commitment to determine the transcriptional changes induced by AP2-G within this sub-population. By analysing more than 18,000 single parasite transcriptomes from a conditional AP2-G knockdown line and NF54 wild-type parasites at multiple stages of development, we show that sexually committed, AP2-G mature schizonts specifically upregulate additional regulators of gene expression, including other AP2 transcription factors, histone-modifying enzymes, and regulators of nucleosome positioning. These epigenetic regulators may act to facilitate the expression and/or repression of genes that are necessary for the initiation of gametocyte development in the subsequent cell cycle.
    Keywords: Sequence Analysis, RNA ; Single-Cell Analysis ; Gametogenesis -- Genetics ; Malaria -- Parasitology ; Plasmodium Falciparum -- Cytology ; Transcriptome -- Genetics
    ISSN: 00280836
    E-ISSN: 1476-4687
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