35 results on '"Rayner, Tim F."'
Search Results
2. Genome-wide methylation analyses of primary human leukocyte subsets identifies functionally important cell-type–specific hypomethylated regions
- Author
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Zilbauer, Matthias, Rayner, Tim F., Clark, Christine, Coffey, Alison J., Joyce, Chris J., Palta, Priit, Palotie, Aarno, Lyons, Paul A., and Smith, Kenneth G.C.
- Published
- 2013
- Full Text
- View/download PDF
3. A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus
- Author
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Willcocks, Lisa C., Carr, Edward J., Niederer, Heather A., Rayner, Tim F., Williams, Thomas N., Yang, Wanling, Scott, J. Anthony G., Urban, Britta C., Peshu, Norbert, Vyse, Timothy J., Lau, Yu Lung, Lyons, Paul A., Smith, Kenneth G. C., and Fearon, Douglas T.
- Published
- 2010
4. Gene expression profiling of [CD8.sup.+] T cells predicts prognosis in patients with Crohn disease and ulcerative colitis
- Author
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Lee, James C., Lyons, Paul A., McKinney, Eoin F., Sowerby, John M., Carr, Edward J., Bredin, Francesca, Rickman, Hannah M., Ratlamwala, Huzefa, Hatton, Alexander, Rayner, Tim F., Parkes, Miles, and Smith, Kenneth G.C.
- Subjects
T cells -- Physiological aspects -- Research ,Gene expression -- Research ,Ulcerative colitis -- Prognosis -- Genetic aspects -- Research ,Crohn's disease -- Prognosis -- Research -- Genetic aspects ,Health care industry - Abstract
Crohn disease (CD) and ulcerative colitis (UC) are increasingly common, chronic forms of inflammatory bowel disease. The behavior of these diseases varies unpredictably among patients. Identification of reliable prognostic biomarkers would enable treatment to be personalized so that patients destined to experience aggressive disease could receive appropriately potent therapies from diagnosis, while those who will experience more indolent disease are not exposed to the risks and side effects of unnecessary immunosuppression. Using transcriptional profiling of circulating T cells isolated from patients with CD and UC, we identified analogous [CD8.sup.+] T cell transcriptional signatures that divided patients into 2 otherwise indistinguishable subgroups. In both UC and CD, patients in these subgroups subsequently experienced very different disease courses. A substantially higher incidence of frequently relapsing disease was experienced by those patients in the subgroup defined by elevated expression of genes involved in antigen-dependent T cell responses, including signaling initiated by both IL-7 and TCR ligation--pathways previously associated with prognosis in unrelated autoimmune diseases. No equivalent correlation was observed with [CD4.sup.+] T cell gene expression. This suggests that the course of otherwise distinct autoimmune and inflammatory conditions may be influenced by common pathways and identifies what we believe to be the first biomarker that can predict prognosis in both UC and CD from diagnosis, a major step toward personalized therapy., Instruction Crohn disease (CD) and ulcerative colitis (UC) are chronic forms of inflammatory bowel disease (IBD) that predominantly affect young adults and cause considerable morbidity. UC typically presents with bloody [...]
- Published
- 2011
- Full Text
- View/download PDF
5. follicular regulatory T cells control the germinal center response
- Author
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Linterman, Michelle A., Pierson, Wim, Lee, Sau K., Kallies, Axel, Kawamoto, Shimpei, Rayner, Tim F., Srivastava, Monika, Divekar, Devina P., Beaton, Laura, Hogan, Jennifer J., Fagarasan, Sidonia, Liston, Adrian, Smith, Kenneth G.C., and Vinuesa, Carola G.
- Subjects
Gene expression -- Research ,T cells -- Physiological aspects -- Research ,Estrone -- Physiological aspects -- Research ,Biological sciences ,Health - Abstract
Follicular helper ([T.sub.FH]) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of [T.sub.FH] numbers maintains self tolerance. We describe a population of [Foxp3.sup.+] [Blimp-1.sup.+] [CD4.sup.+] T cells constituting 10-25% of the CXCR5 high [PD-1.sup.high] [CD4.sup.+] T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T ([T.sub.FR]) cells share phenotypic characteristics with [T.sub.FH] and conventional [Foxp3.sup.+] regulatory T ([T.sub.reg]) cells yet are distinct from both. Similar to [T.sub.FH] cells, [T.sub.FR] cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, [T.sub.FR] cells originate from thymic-derived [Foxp3.sup.+] precursors, not naive or [T.sub.FH] cells. [T.sub.FR] cells are suppressive in vitro and limit [T.sub.FH] cell and germinal center B cell numbers in vivo. In the absence of [T.sub.FR] cells, an outgrowth of non--antigen-specific B cells in germinal centers leads to fewer antigen- specific cells. Thus, the [T.sub.FH] differentiation pathway is co-opted by [T.sub.reg] cells to control the germinal center response., Germinal centers are clusters of rapidly dividing B cells formed in secondary lymphoid tissues in response to T-dependent antigens. Within the germinal center, mutation of the B receptor cell V-region [...]
- Published
- 2011
- Full Text
- View/download PDF
6. Pervasive lesion segregation shapes cancer genome evolution
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Aitken, Sarah J., Anderson, Craig J., Connor, Frances, Pich, Oriol, Sundaram, Vasavi, Feig, Christine, Rayner, Tim F., Lukk, Margus, Aitken, Stuart, Luft, Juliet, Kentepozidou, Elissavet, Arnedo-Pac, Claudia, Beentjes, Sjoerd V., Davies, Susan E., Drews, Ruben M., Ewing, Ailith, Kaiser, Vera B., Khamseh, Ava, López-Arribillaga, Erika, Redmond, Aisling M., Santoyo-Lopez, Javier, Sentís, Inés, Talmane, Lana, Yates, Andrew D., Flicek, Paul, López-Bigas, Núria, Odom, Duncan T., Semple, Colin A., Taylor, Martin S., Aitken, Sarah [0000-0002-1897-4140], Connor, Frances [0000-0003-2858-9411], and Apollo - University of Cambridge Repository
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Male ,DNA Repair ,Transcription, Genetic ,Cell division ,Genome ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Chromosome Segregation ,Neoplasms ,Cancer genomics ,Genetics ,0303 health sciences ,Multidisciplinary ,Liver Neoplasms ,Cell cycle ,3. Good health ,ErbB Receptors ,raf Kinases ,medicine.symptom ,Signal Transduction ,DNA Replication ,Tumour heterogeneity ,DNA repair ,Base pair ,DNA damage ,Sister chromatid exchange ,Biology ,Lesion ,Evolution, Molecular ,03 medical and health sciences ,medicine ,Animals ,Humans ,Allele ,Selection, Genetic ,Alleles ,030304 developmental biology ,DNA replication ,Cancer ,DNA adducts ,medicine.disease ,Nucleotide excision repair ,chemistry ,Mutation ,ras Proteins ,Sister Chromatid Exchange ,DNA ,030217 neurology & neurosurgery - Abstract
SummaryCancers arise through the acquisition of oncogenic mutations and grow through clonal expansion1, 2. Here we reveal that most mutagenic DNA lesions are not resolved as mutations within a single cell-cycle. Instead, DNA lesions segregate unrepaired into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterise this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can generate multiple alternative alleles in successive cell divisions, thereby increasing both multi-allelic and combinatorial genetic diversity. The phasing of lesions enables the accurate measurement of strand biased repair processes, the quantification of oncogenic selection, and the fine mapping of sister chromatid exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.
- Published
- 2019
- Full Text
- View/download PDF
7. Genetically Distinct Subsets within ANCA-Associated Vasculitis
- Author
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Lyons, Paul A., Rayner, Tim F., Trivedi, Sapna, Holle, Julia U., Watts, Richard A., Jayne, David R.W., Baslund, Bo, Brenchley, Paul, Bruchfeld, Annette, Chaudhry, Afzal N., Cohen Tervaert, Jan Willem, Deloukas, Panos, Feighery, Conleth, Gross, Wolfgang L., Guillevin, Loic, Gunnarsson, Iva, Harper, Lorraine, Hrušková, Zdenka, Little, Mark A., Martorana, Davide, Neumann, Thomas, Ohlsson, Sophie, Padmanabhan, Sandosh, Pusey, Charles D., Salama, Alan D., Sanders, Jan-Stephan F., Savage, Caroline O., Segelmark, Mårten, Stegeman, Coen A., Tesař, Vladimir, Vaglio, Augusto, Wieczorek, Stefan, Wilde, Benjamin, Zwerina, Jochen, Rees, Andrew J., Clayton, David G., and Smith, Kenneth G.C.
- Published
- 2012
8. Copy number, linkage disequilibrium and disease association in the FCGR locus
- Author
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Niederer, Heather A., Willcocks, Lisa C., Rayner, Tim F., Yang, Wanling, Lau, Yu Lung, Williams, Thomas N., Scott, J. Anthony, Urban, Britta C., Peshu, Norbert, Dunstan, Sarah J., Hien, Tran Tinh, Phu, Nguyen Hoan, Padyukov, Leonid, Gunnarsson, Iva, Svenungsson, Elisabet, Savage, Caroline O., Watts, Richard A., Lyons, Paul A., Clayton, David G., and Smith, Kenneth G.C.
- Published
- 2010
- Full Text
- View/download PDF
9. Pervasive lesion segregation shapes cancer genome evolution
- Author
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Aitken, Sarah J., primary, Anderson, Craig J., additional, Connor, Frances, additional, Pich, Oriol, additional, Sundaram, Vasavi, additional, Feig, Christine, additional, Rayner, Tim F., additional, Lukk, Margus, additional, Aitken, Stuart, additional, Luft, Juliet, additional, Kentepozidou, Elissavet, additional, Arnedo-Pac, Claudia, additional, Beentjes, Sjoerd, additional, Davies, Susan E., additional, Drews, Ruben M., additional, Ewing, Ailith, additional, Kaiser, Vera B., additional, Khamseh, Ava, additional, López-Arribillaga, Erika, additional, Redmond, Aisling M., additional, Santoyo-Lopez, Javier, additional, Sentís, Inés, additional, Talmane, Lana, additional, Yates, Andrew D., additional, Semple, Colin A., additional, López-Bigas, Núria, additional, Flicek, Paul, additional, Odom, Duncan T., additional, and Taylor, Martin S., additional
- Published
- 2019
- Full Text
- View/download PDF
10. Novel expression signatures identified by transcriptional analysis of separated leucocyte subsets in systemic lupus erythematosus and vasculitis
- Author
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Lyons, Paul A, McKinney, Eoin F, Rayner, Tim F, Hatton, Alexander, Woffendin, Hayley B, Koukoulaki, Maria, Freeman, Thomas C, Jayne, David R, Chaudhry, Afzal N, and Smith, Kenneth G
- Published
- 2010
- Full Text
- View/download PDF
11. Importing ArrayExpress datasets into R/Bioconductor
- Author
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Kauffmann, Audrey, Rayner, Tim F., Parkinson, Helen, Kapushesky, Misha, Lukk, Margus, Brazma, Alvis, and Huber, Wolfgang
- Published
- 2009
12. MAGETabulator, a suite of tools to support the microarray data format MAGE-TAB
- Author
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Rayner, Tim F., Rezwan, Faisal Ibne, Lukk, Margus, Bradley, Xiangqun Zheng, Farne, Anna, Holloway, Ele, Malone, James, Williams, Eleanor, and Parkinson, Helen
- Published
- 2009
13. ArrayExpress update—from an archive of functional genomics experiments to the atlas of gene expression
- Author
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Parkinson, Helen, Kapushesky, Misha, Kolesnikov, Nikolay, Rustici, Gabriella, Shojatalab, Mohammad, Abeygunawardena, Niran, Berube, Hugo, Dylag, Miroslaw, Emam, Ibrahim, Farne, Anna, Holloway, Ele, Lukk, Margus, Malone, James, Mani, Roby, Pilicheva, Ekaterina, Rayner, Tim F., Rezwan, Faisal, Sharma, Anjan, Williams, Eleanor, Bradley, Xiangqun Zheng, Adamusiak, Tomasz, Brandizi, Marco, Burdett, Tony, Coulson, Richard, Krestyaninova, Maria, Kurnosov, Pavel, Maguire, Eamonn, Neogi, Sudeshna Guha, Rocca-Serra, Philippe, Sansone, Susanna-Assunta, Sklyar, Nataliya, Zhao, Mengyao, Sarkans, Ugis, and Brazma, Alvis
- Published
- 2009
14. Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis
- Author
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Lee, James C, Lyons, Paul A, McKinney, Eoin F, Sowerby, John M, Carr, Edward J, Bredin, Francesca, Rickman, Hannah M, Ratlamwala, Huzefa, Hatton, Alexander, Rayner, Tim F, Parkes, Miles, and Smith, Kenneth GC
- Subjects
Adult ,Male ,Interleukin-7 ,Receptors, Antigen, T-Cell ,CD8-Positive T-Lymphocytes ,Middle Aged ,Prognosis ,Crohn Disease ,Humans ,Colitis, Ulcerative ,Female ,Prospective Studies ,Transcriptome ,Signal Transduction - Abstract
Crohn disease (CD) and ulcerative colitis (UC) are increasingly common, chronic forms of inflammatory bowel disease. The behavior of these diseases varies unpredictably among patients. Identification of reliable prognostic biomarkers would enable treatment to be personalized so that patients destined to experience aggressive disease could receive appropriately potent therapies from diagnosis, while those who will experience more indolent disease are not exposed to the risks and side effects of unnecessary immunosuppression. Using transcriptional profiling of circulating T cells isolated from patients with CD and UC, we identified analogous CD8+ T cell transcriptional signatures that divided patients into 2 otherwise indistinguishable subgroups. In both UC and CD, patients in these subgroups subsequently experienced very different disease courses. A substantially higher incidence of frequently relapsing disease was experienced by those patients in the subgroup defined by elevated expression of genes involved in antigen-dependent T cell responses, including signaling initiated by both IL-7 and TCR ligation - pathways previously associated with prognosis in unrelated autoimmune diseases. No equivalent correlation was observed with CD4+ T cell gene expression. This suggests that the course of otherwise distinct autoimmune and inflammatory conditions may be influenced by common pathways and identifies what we believe to be the first biomarker that can predict prognosis in both UC and CD from diagnosis, a major step toward personalized therapy.
- Published
- 2018
- Full Text
- View/download PDF
15. A simple spreadsheet-based, MIAME-supportive format for microarray data: MAGE-TAB
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White Joseph, Stoeckert Christian J, Sherlock Gavin, Quackenbush John, Petersen Kjell, Miller Michael, Maier Donald S, Liu Junmin, Irizarry Rafael A, Holloway Ele, Farne Anna, Causton Helen C, Spellman Paul T, Rocca-Serra Philippe, Rayner Tim F, Whetzel Patricia L, Wymore Farrell, Parkinson Helen, Sarkans Ugis, Ball Catherine A, and Brazma Alvis
- Subjects
Computer applications to medicine. Medical informatics ,R858-859.7 ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Sharing of microarray data within the research community has been greatly facilitated by the development of the disclosure and communication standards MIAME and MAGE-ML by the MGED Society. However, the complexity of the MAGE-ML format has made its use impractical for laboratories lacking dedicated bioinformatics support. Results We propose a simple tab-delimited, spreadsheet-based format, MAGE-TAB, which will become a part of the MAGE microarray data standard and can be used for annotating and communicating microarray data in a MIAME compliant fashion. Conclusion MAGE-TAB will enable laboratories without bioinformatics experience or support to manage, exchange and submit well-annotated microarray data in a standard format using a spreadsheet. The MAGE-TAB format is self-contained, and does not require an understanding of MAGE-ML or XML.
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- 2006
- Full Text
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16. Pervasive lesion segregation shapes cancer genome evolution.
- Author
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Aitken, Sarah J., Anderson, Craig J., Connor, Frances, Pich, Oriol, Sundaram, Vasavi, Feig, Christine, Rayner, Tim F., Lukk, Margus, Aitken, Stuart, Luft, Juliet, Kentepozidou, Elissavet, Arnedo-Pac, Claudia, Beentjes, Sjoerd V., Davies, Susan E., Drews, Ruben M., Ewing, Ailith, Kaiser, Vera B., Khamseh, Ava, López-Arribillaga, Erika, and Redmond, Aisling M.
- Abstract
Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion1,2. Here we reveal that most mutagenic DNA lesions are not resolved into a mutated DNA base pair within a single cell cycle. Instead, DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterize this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multiallelic and combinatorial genetic diversity. The phasing of lesions enables accurate measurement of strand-biased repair processes, quantification of oncogenic selection and fine mapping of sister-chromatid-exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes. Mutagenic lesions such as those that give rise to cancer frequently segregate—unrepaired—during cell division, resulting in phasing of multiple alleles across generations of daughter cells and consequent tumour heterogeneity. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
17. Mutational landscape of a chemically-induced mouse model of liver cancer
- Author
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Connor, Frances, primary, Rayner, Tim F., additional, Feig, Christine, additional, Aitken, Sarah J., additional, Lukk, Margus, additional, and Odom, Duncan T., additional
- Published
- 2018
- Full Text
- View/download PDF
18. Interplay of cis and trans mechanisms driving transcription factor binding and gene expression evolution
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Wong, Emily S., primary, Schmitt, Bianca M., additional, Kazachenka, Anastasiya, additional, Thybert, David, additional, Redmond, Aisling, additional, Connor, Frances, additional, Rayner, Tim F., additional, Feig, Christine, additional, Ferguson-Smith, Anne C., additional, Marioni, John C., additional, Odom, Duncan T., additional, and Flicek, Paul, additional
- Published
- 2017
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- View/download PDF
19. Foxp3+ follicular regulatory T cells control T follicular helper cells and the germinal center response
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Linterman, Michelle A., Pierson, Wim, Lee, Sau K., Kallies, Axel, Kawamoto, Shimpei, Rayner, Tim F., Srivastava, Monika, Divekar, Devina P., Beaton, Laura, Hogan, Jennifer J., Fagarasan, Sidonia, Liston, Adrian, Smith, Kenneth G. C., and Vinuesa, Carola G.
- Subjects
Article - Abstract
Follicular helper (TFH) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of TFH numbers maintains self-tolerance. We describe a population of Foxp3+Blimp-1+CD4+ T cells constituting 10-25% of the CXCR5highPD-1highCD4+ T cells found in germinal center after immunization. These follicular regulatory T cells (TFR) share phenotypic characteristics with TFH and conventional Foxp3+ regulatory T cells (Treg) yet are distinct from either. Similar to TFH cells, TFR development depends on Bcl-6, SAP, CD28 and B cells; however TFR originate from thymic-derived Foxp3+ precursors, not naïve or TFH cells. TFR are suppressive in vitro and limit TFH and germinal center B cell numbers in vivo. In the absence of TFR, an outgrowth of non-antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, Treg cells use the TFH differentiation pathway to produce specialized suppressor cells that control the germinal center response.
- Published
- 2011
20. Enhancer evolution across 20 mammalian species
- Author
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Villar, Diego, Berthelot, Camille, Aldridge, Sarah, Rayner, Tim F, Lukk, Margus, Pignatelli, Miguel, Park, Thomas J, Deaville, Robert, Erichsen, Jonathan T, Jasinska, Anna J, Turner, James MA, Bertelsen, Mads F, Murchison, Elizabeth P, Flicek, Paul, Odom, Duncan T, Murchison, Elizabeth [0000-0001-7462-8907], Odom, Duncan [0000-0001-6201-5599], and Apollo - University of Cambridge Repository
- Subjects
Evolution, Molecular ,Histone Code ,Mammals ,Enhancer Elements, Genetic ,Liver ,Biochemistry, Genetics and Molecular Biology(all) ,Animals ,Humans ,RE ,Promoter Regions, Genetic ,Transcription Factors - Abstract
SummaryThe mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially or fully conserved across these species. Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences. These results provide important insight into the functional genetics underpinning mammalian regulatory evolution.
- Published
- 2015
21. Interplay of cis and trans mechanisms driving transcription factor binding and gene expression evolution
- Author
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Wong, Emily S, primary, Schmitt, Bianca M, additional, Kazachenka, Anastasiya, additional, Thybert, David, additional, Redmond, Aisling, additional, Connor, Frances, additional, Rayner, Tim F., additional, Feig, Christine, additional, Ferguson-Smith, Anne C., additional, Marioni, John C, additional, Odom, Duncan T, additional, and Flicek, Paul, additional
- Published
- 2016
- Full Text
- View/download PDF
22. MiR-210 is induced by Oct-2, regulates B-cells and inhibits autoantibody production1
- Author
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Mok, Yingting, Schwierzeck, Vera, Thomas, David C., Vigorito, Elena, Rayner, Tim F., Jarvis, Lorna B., Prosser, Haydn M., Bradley, Allan, Withers, David R., Mårtensson, Inga-Lill, Corcoran, Lynn M., Blenkiron, Cherie, Miska, Eric A., Lyons, Paul A., and Smith, Kenneth G.C.
- Subjects
B-Lymphocytes ,Chromatin Immunoprecipitation ,Fluorescent Antibody Technique ,Enzyme-Linked Immunosorbent Assay ,Mice, Transgenic ,Cell Separation ,Lymphocyte Activation ,Polymerase Chain Reaction ,Article ,Mice, Inbred C57BL ,Mice ,MicroRNAs ,Animals ,Octamer Transcription Factor-2 ,Transcriptome ,Autoantibodies ,Oligonucleotide Array Sequence Analysis - Abstract
MicroRNAs (MiRs) are small, noncoding RNAs that regulate gene expression posttranscriptionally. In this study, we show that MiR-210 is induced by Oct-2, a key transcriptional mediator of B cell activation. Germline deletion of MiR-210 results in the development of autoantibodies from 5 mo of age. Overexpression of MiR-210 in vivo resulted in cell autonomous expansion of the B1 lineage and impaired fitness of B2 cells. Mice overexpressing MiR-210 exhibited impaired class-switched Ab responses, a finding confirmed in wild-type B cells transfected with a MiR-210 mimic. In vitro studies demonstrated defects in cellular proliferation and cell cycle entry, which were consistent with the transcriptomic analysis demonstrating downregulation of genes involved in cellular proliferation and B cell activation. These findings indicate that Oct-2 induction of MiR-210 provides a novel inhibitory mechanism for the control of B cells and autoantibody production.
- Published
- 2013
23. Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis
- Author
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Lee, James C, Lyons, Paul A, McKinney, Eoin F, Sowerby, John M, Carr, Edward J, Bredin, Francesca, Rickman, Hannah M, Ratlamwala, Huzefa, Hatton, Alexander, Rayner, Tim F, Parkes, Miles, Smith, Kenneth GC, Lee, James [0000-0001-5711-9385], Lyons, Paul [0000-0001-7035-8997], McKinney, Eoin [0000-0003-3516-3072], Carr, Edward [0000-0001-9343-4593], Parkes, Miles [0000-0002-6467-0631], Smith, Kenneth [0000-0003-3829-4326], and Apollo - University of Cambridge Repository
- Subjects
Adult ,Male ,Interleukin-7 ,Receptors, Antigen, T-Cell ,CD8-Positive T-Lymphocytes ,Middle Aged ,Prognosis ,Crohn Disease ,Humans ,Colitis, Ulcerative ,Female ,Prospective Studies ,Transcriptome ,Signal Transduction - Abstract
Crohn disease (CD) and ulcerative colitis (UC) are increasingly common, chronic forms of inflammatory bowel disease. The behavior of these diseases varies unpredictably among patients. Identification of reliable prognostic biomarkers would enable treatment to be personalized so that patients destined to experience aggressive disease could receive appropriately potent therapies from diagnosis, while those who will experience more indolent disease are not exposed to the risks and side effects of unnecessary immunosuppression. Using transcriptional profiling of circulating T cells isolated from patients with CD and UC, we identified analogous CD8+ T cell transcriptional signatures that divided patients into 2 otherwise indistinguishable subgroups. In both UC and CD, patients in these subgroups subsequently experienced very different disease courses. A substantially higher incidence of frequently relapsing disease was experienced by those patients in the subgroup defined by elevated expression of genes involved in antigen-dependent T cell responses, including signaling initiated by both IL-7 and TCR ligation - pathways previously associated with prognosis in unrelated autoimmune diseases. No equivalent correlation was observed with CD4+ T cell gene expression. This suggests that the course of otherwise distinct autoimmune and inflammatory conditions may be influenced by common pathways and identifies what we believe to be the first biomarker that can predict prognosis in both UC and CD from diagnosis, a major step toward personalized therapy.
- Published
- 2011
24. MiR-210 Is Induced by Oct-2, Regulates B Cells, and Inhibits Autoantibody Production
- Author
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Mok, Yingting, primary, Schwierzeck, Vera, additional, Thomas, David C., additional, Vigorito, Elena, additional, Rayner, Tim F., additional, Jarvis, Lorna B., additional, Prosser, Haydn M., additional, Bradley, Allan, additional, Withers, David R., additional, Mårtensson, Inga-Lill, additional, Corcoran, Lynn M., additional, Blenkiron, Cherie, additional, Miska, Eric A., additional, Lyons, Paul A., additional, and Smith, Kenneth G. C., additional
- Published
- 2013
- Full Text
- View/download PDF
25. Signatures of CD4 T-cell help and CD8 exhaustion predict clinical outcome in autoimmunity, infection, and vaccination
- Author
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McKinney, Eoin F, primary, Lee, James, additional, Lyons, Paul A, additional, Rayner, Tim F, additional, Carr, Edward J, additional, Hatton, Alexander, additional, Jayne, David RW, additional, Willcocks, Lisa C, additional, Chaudhry, Afzal N, additional, and Smith, Kenneth GC, additional
- Published
- 2013
- Full Text
- View/download PDF
26. Foxp3+ follicular regulatory T cells control the germinal center response
- Author
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Linterman, Michelle A, primary, Pierson, Wim, additional, Lee, Sau K, additional, Kallies, Axel, additional, Kawamoto, Shimpei, additional, Rayner, Tim F, additional, Srivastava, Monika, additional, Divekar, Devina P, additional, Beaton, Laura, additional, Hogan, Jennifer J, additional, Fagarasan, Sidonia, additional, Liston, Adrian, additional, Smith, Kenneth G C, additional, and Vinuesa, Carola G, additional
- Published
- 2011
- Full Text
- View/download PDF
27. Novel expression signatures identified by transcriptional analysis of separated leucocyte subsets in systemic lupus erythematosus and vasculitis
- Author
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Lyons, Paul A, primary, McKinney, Eoin F, additional, Rayner, Tim F, additional, Hatton, Alexander, additional, Woffendin, Hayley B, additional, Koukoulaki, Maria, additional, Freeman, Thomas C, additional, Jayne, David R W, additional, Chaudhry, Afzal N, additional, and Smith, Kenneth G C, additional
- Published
- 2009
- Full Text
- View/download PDF
28. MAGETabulator, a suite of tools to support the microarray data format MAGE-TAB
- Author
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Rayner, Tim F., primary, Rezwan, Faisal Ibne, additional, Lukk, Margus, additional, Bradley, Xiangqun Zheng, additional, Farne, Anna, additional, Holloway, Ele, additional, Malone, James, additional, Williams, Eleanor, additional, and Parkinson, Helen, additional
- Published
- 2008
- Full Text
- View/download PDF
29. A simple spreadsheet-based, MIAME-supportive format for microarray data: MAGE-TAB
- Author
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Rayner, Tim F, primary, Rocca-Serra, Philippe, additional, Spellman, Paul T, additional, Causton, Helen C, additional, Farne, Anna, additional, Holloway, Ele, additional, Irizarry, Rafael A, additional, Liu, Junmin, additional, Maier, Donald S, additional, Miller, Michael, additional, Petersen, Kjell, additional, Quackenbush, John, additional, Sherlock, Gavin, additional, Stoeckert, Christian J, additional, White, Joseph, additional, Whetzel, Patricia L, additional, Wymore, Farrell, additional, Parkinson, Helen, additional, Sarkans, Ugis, additional, Ball, Catherine A, additional, and Brazma, Alvis, additional
- Published
- 2006
- Full Text
- View/download PDF
30. A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus.
- Author
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Wilicocks, Lisa C., Carr, Edward J., Niederer, Heather A., Rayner, Tim F., WiIIiams, Thomas N., Wanling Yang, Scott, J. Anthony G., Urban, Britta C., Peshu, Norbert, Vyse, Timothy J., Yu Lung Lau, Lyons, Paul A., and Smith, Kenneth G. C.
- Subjects
SYSTEMIC lupus erythematosus ,FC receptors ,GENE frequency ,MALARIA prevention ,CAUCASIAN race ,SOUTHEAST Asians - Abstract
Systemic lupus erythematosus (SLE) is a muttisystem autoimmune disease more prevalent in people of African and Asian origin than Caucasian origin. FcγRllb is an inhibitory Fc receptor .with a critical role in immune regulation. Mouse data suggest that FcγRllb deficiency increases susceptibility to autoimmune disease but protects against infection. We show that a SNP in human FCGR2B that abrogates receptor function is strongly associated with susceptibility to SLE in both Caucasians and Southeast Asians. The minor allele of this SNP is more common in Southeast Asians and Africans. populations from areas where malaria is endemic, than in Caucasians. We show that homozygosity for the minor allele is associated with substantial protection against severe malaria in an East African population (odds ratio = 0.56; P = 7.1 x 10
-5 ). This protective effect against malaria may contribute to the higher frequency of this SNP and hence, SLE in Africans and Southeast Asians. [ABSTRACT FROM AUTHOR]- Published
- 2010
31. Copy number, linkage disequilibrium and disease association in the FCGR locus
- Author
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Niederer, Heather A, Willcocks, Lisa C, Rayner, Tim F, Yang, Wanling, Lau, Yu Lung, Williams, Thomas N, Scott, J Anthony G, Urban, Britta C, Peshu, Norbert, Dunstan, Sarah J, Hien, Tran Tinh, Phu, Nguyen Hoan, Padyukov, Leonid, Gunnarsson, Iva, Svenungsson, Elisabet, Savage, Caroline O, Watts, Richard A, Lyons, Paul A, Clayton, David G, and Smith, Kenneth GC
- Subjects
Sweden ,China ,Chi-Square Distribution ,Genotype ,Receptors, IgG ,Gene Dosage ,Black People ,GPI-Linked Proteins ,Kenya ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,United Kingdom ,White People ,3. Good health ,Asian People ,Gene Frequency ,Vietnam ,Humans ,Lupus Erythematosus, Systemic ,Genetic Predisposition to Disease ,Alleles - Abstract
The response of a leukocyte to immune complexes (ICs) is modulated by receptors for the Fc region of IgG (FcgammaRs), and alterations in their affinity or function have been associated with risk of autoimmune diseases, including systemic lupus erythematosus (SLE). The low-affinity FcgammaR genomic locus is complex, containing regions of copy number variation (CNV) which can alter receptor expression and leukocyte responses to IgG. Combined paralogue ratio tests (PRTs) were used to distinguish three intervals within the FCGR locus which undergo CNV, and to determine FCGR gene copy number (CN). There were significant differences in FCGR3B and FCGR3A CNV profiles between Caucasian, East Asian and Kenyan populations. A previously noted association of low FCGR3B CN with SLE in Caucasians was supported [OR = 1.57 (1.08-2.27), P = 0.018], and replicated in Chinese [OR = 1.65 (1.25-2.18), P = 4 x 10(-4)]. There was no association of FCGR3B CNV with vasculitis, nor with malarial or bacterial infection. Linkage disequilibrium (LD) between multi-allelic FCGR3B CNV and SLE-associated SNPs in the FCGR locus was defined for the first time. Despite LD between FCGR3B CNV and a variant in FcgammaRIIB (I232T) which abolishes inhibitory function, both reduced CN of FCGR3B and homozygosity of the FcgammaRIIB-232T allele were individually strongly associated with SLE risk. Thus CN of FCGR3B, which controls IC responses and uptake by neutrophils, and variations in FCGR2B, which controls factors such as antibody production and macrophage activation, are important in SLE pathogenesis. Further interpretations of contributions to pathogenesis by FcgammaRs must be made in the context of LD involving CNV regions.
32. Mutational landscape of a chemically-induced mouse model of liver cancer
- Author
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Connor, Frances, Rayner, Tim F, Aitken, Sarah J, Feig, Christine, Lukk, Margus, Santoyo-Lopez, Javier, and Odom, Duncan T
- Subjects
Male ,Mice, Inbred C3H ,DNA Copy Number Variations ,Hepatocellular carcinoma ,Mutational signatures ,Carcinogen mouse model ,3. Good health ,Hras ,Disease Models, Animal ,Mice ,Genes, ras ,Liver Neoplasms, Experimental ,Mutation ,Cancer genomics ,Animals ,Diethylnitrosamine ,Exome - Abstract
BACKGROUND & AIMS: Carcinogen-induced mouse models of liver cancer are used extensively to study the pathogenesis of the disease and are critical for validating candidate therapeutics. These models can recapitulate molecular and histological features of human disease. However, it is not known if the genomic alterations driving these mouse tumour genomes are comparable to those found in human tumours. Herein, we provide a detailed genomic characterisation of tumours from a commonly used mouse model of hepatocellular carcinoma (HCC). METHODS: We analysed whole exome sequences of liver tumours arising in mice exposed to diethylnitrosamine (DEN). Mutational signatures were compared between liver tumours from DEN-treated and untreated mice, and human HCCs. RESULTS: DEN-initiated tumours had a high, uniform number of somatic single nucleotide variants (SNVs), with few insertions, deletions or copy number alterations, consistent with the known genotoxic action of DEN. Exposure of hepatocytes to DEN left a reproducible mutational imprint in resulting tumour exomes which we could computationally reconstruct using six known COSMIC mutational signatures. The tumours carried a high diversity of low-incidence, non-synonymous point mutations in many oncogenes and tumour suppressors, reflecting the stochastic introduction of SNVs into the hepatocyte genome by the carcinogen. We identified four recurrently mutated genes that were putative oncogenic drivers of HCC in this model. Every neoplasm carried activating hotspot mutations either in codon 61 of Hras, in codon 584 of Braf or in codon 254 of Egfr. Truncating mutations of Apc occurred in 21% of neoplasms, which were exclusively carcinomas supporting a role for deregulation of Wnt/β-catenin signalling in cancer progression. CONCLUSIONS: Our study provides detailed insight into the mutational landscape of tumours arising in a commonly used carcinogen model of HCC, facilitating the future use of this model to better understand the human disease. LAY SUMMARY: Mouse models are widely used to study the biology of cancer and to test potential therapies. Herein, we have described the mutational landscape of tumours arising in a carcinogen-induced mouse model of liver cancer. Since cancer is a disease caused by genomic alterations, information about the patterns and types of mutations in the tumours in this mouse model should facilitate its use to study human liver cancer.
33. Pervasive lesion segregation shapes cancer genome evolution
- Author
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Aitken, Sarah J, Anderson, Craig J, Connor, Frances, Pich, Oriol, Sundaram, Vasavi, Feig, Christine, Rayner, Tim F, Lukk, Margus, Aitken, Stuart, Luft, Juliet, Kentepozidou, Elissavet, Arnedo-Pac, Claudia, Beentjes, Sjoerd, Davies, Susan E, Drews, Ruben M, Ewing, Ailith, Kaiser, Vera B, Khamseh, Ava, López-Arribillaga, Erika, Redmond, Aisling M, Santoyo-Lopez, Javier, Sentís, Inés, Talmane, Lana, Yates, Andrew D, Semple, Colin A, López-Bigas, Núria, Flicek, Paul, Odom, Duncan T, and Taylor, Martin S
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DNA Replication ,Male ,Genome ,DNA Repair ,Transcription, Genetic ,Liver Neoplasms ,3. Good health ,ErbB Receptors ,Evolution, Molecular ,Mice ,Chromosome Segregation ,Neoplasms ,Mutation ,ras Proteins ,Animals ,Humans ,raf Kinases ,Selection, Genetic ,Sister Chromatid Exchange ,Alleles ,Signal Transduction - Abstract
Cancers arise through the acquisition of oncogenic mutations and grow through clonal expansion. Here we reveal that most mutagenic DNA lesions are not resolved as mutations within a single cell-cycle. Instead, DNA lesions segregate unrepaired into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterise this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multi-allelic and combinatorial genetic diversity. The phasing of lesions enables the accurate measurement of strand biased repair processes, quantification of oncogenic selection, and fine mapping of sister chromatid exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.
34. MiR-210 Is Induced by Oct-2, Regulates B Cells, and Inhibits Autoantibody Production.
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Yingting Mok, Schwierzeck, Vera, Thomas, David C., Vigorito, Elena, Rayner, Tim F., Jarvis, Lorna B., Prosser, Haydn M., Bradley, Allan, Withers, David R., Mårtensson, Inga-Lill, Corcoran, Lynn M., Blenkiron, Cherie, Miska, Eric A., Lyons, Paul A., and Smith, Kenneth G. C.
- Subjects
- *
MICRORNA , *B cells , *AUTOANTIBODIES , *TRANSCRIPTION factors , *GENETIC overexpression , *CELL proliferation , *CELL cycle - Abstract
MicroRNAs (MiRs) are small, noncoding RNAs that regulate gene expression posttranscriptionally. In this study, we show that MiR-210 is induced by Oct-2, a key transcriptional mediator of B cell activation. Germline deletion of MiR-210 results in the development of autoantibodies from 5 mo of age. Overexpression of MiR-210 in vivo resulted in cell autonomous expansion of the B1 lineage and impaired fitness of B2 cells. Mice overexpressing MiR-210 exhibited impaired class-switched Ab responses, a finding confirmed in wild-type B cells transfected with a MiR-210 mimic. In vitro studies demonstrated defects in cellular proliferation and cell cycle entry, which were consistent with the transcriptomic analysis demonstrating downregulation of genes involved in cellular proliferation and B cell activation. These findings indicate that Oct-2 induction of MiR-210 provides a novel inhibitory mechanism for the control of B cells and autoantibody production. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
35. Enhancer evolution across 20 mammalian species.
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Villar D, Berthelot C, Aldridge S, Rayner TF, Lukk M, Pignatelli M, Park TJ, Deaville R, Erichsen JT, Jasinska AJ, Turner JM, Bertelsen MF, Murchison EP, Flicek P, and Odom DT
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- Animals, Histone Code, Humans, Transcription Factors metabolism, Enhancer Elements, Genetic, Evolution, Molecular, Liver metabolism, Mammals classification, Mammals genetics, Promoter Regions, Genetic
- Abstract
The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially or fully conserved across these species. Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences. These results provide important insight into the functional genetics underpinning mammalian regulatory evolution., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
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