PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-11 (11)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
1.  Enhancer Evolution across 20 Mammalian Species 
Cell  2015;160(3):554-566.
Summary
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.
Graphical Abstract
Highlights
•Rapid enhancer and slow promoter evolution across genomes of 20 mammalian species•Enhancers are rarely conserved across these mammals•Recently evolved enhancers dominate mammalian regulatory landscapes•Unbiased mapping links candidate enhancers with lineage-specific positive selection
Comparative functional genomic analysis in 20 mammalian species reveals distinct features for the evolution of enhancers, in comparison to those of promoters, across 180 million years.
doi:10.1016/j.cell.2015.01.006
PMCID: PMC4313353  PMID: 25635462
2.  MiR-210 is induced by Oct-2, regulates B-cells and inhibits autoantibody production1 
MicroRNAs are small, non-coding RNAs that regulate gene expression post-transcriptionally. Here, 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 months of age. Overexpression of miR-210 in vivo resulted in cell autonomous expansion of the B1 lineage and impaired fitness of B2 cells. Mice over-expressing miR-210 exhibited impaired class-switched antibody responses, a finding confirmed in wild-type B-cells transfected with a miR-210 mimic. In vitro studies demonstrated a defect in cellular proliferation and cell-cycle entry, which was consistent with the transcriptomic analysis demonstrating down-regulation 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.
doi:10.4049/jimmunol.1301289
PMCID: PMC4162006  PMID: 23960236
3.  Genetically Distinct Subsets within ANCA-Associated Vasculitis 
The New England journal of medicine  2012;367(3):214-223.
BACKGROUND
Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis.
METHODS
A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria.
RESULTS
We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti–proteinase 3 ANCA was associated with HLA-DP and the genes encoding α1-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P = 6.2×10−89, P = 5.6×10−12, and P = 2.6×10−7, respectively). Anti–myeloperoxidase ANCA was associated with HLA-DQ (P = 2.1×10−8).
CONCLUSIONS
This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA–associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA–associated vasculitis and myeloperoxidase ANCA–associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.)
doi:10.1056/NEJMoa1108735
PMCID: PMC3773907  PMID: 22808956
4.  Foxp3+ follicular regulatory T cells control T follicular helper cells and the germinal center response 
Nature medicine  2011;17(8):975-982.
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.
doi:10.1038/nm.2425
PMCID: PMC3182542  PMID: 21785433
5.  Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis  
The Journal of Clinical Investigation  2011;121(10):4170-4179.
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.
doi:10.1172/JCI59255
PMCID: PMC3196314  PMID: 21946256
6.  Novel expression signatures identified by transcriptional analysis of separated leucocyte subsets in systemic lupus erythematosus and vasculitis 
Annals of the Rheumatic Diseases  2010;69(6):1208-1213.
Objective
To optimise a strategy for identifying gene expression signatures differentiating systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibody-associated vasculitis that provide insight into disease pathogenesis and identify biomarkers.
Methods
44 vasculitis patients, 13 SLE patients and 25 age and sex-matched controls were enrolled. CD4 and CD8 T cells, B cells, monocytes and neutrophils were isolated from each patient and, together with unseparated peripheral blood mononuclear cells (PBMC), were hybridised to spotted oligonucleotide microarrays.
Results
Using expression data obtained from purified cells a substantial number of differentially expressed genes were identified that were not detectable in the analysis of PBMC. Analysis of purified T cells identified a SLE-associated, CD4 T-cell signature consistent with type 1 interferon signalling driving the generation and survival of tissue homing T cells and thereby contributing to disease pathogenesis. Moreover, hierarchical clustering using expression data from purified monocytes provided significantly improved discrimination between the patient groups than that obtained using PBMC data, presumably because the differentially expressed genes reflect genuine differences in processes underlying disease pathogenesis.
Conclusion
Analysis of leucocyte subsets enabled the identification of gene signatures of both pathogenic relevance and with better disease discrimination than those identified in PBMC. This approach thus provides substantial advantages in the search for diagnostic and prognostic biomarkers in autoimmune disease.
doi:10.1136/ard.2009.108043
PMCID: PMC2935323  PMID: 19815495
7.  Copy number, linkage disequilibrium and disease association in the FCGR locus 
Human Molecular Genetics  2010;19(16):3282-3294.
The response of a leukocyte to immune complexes (ICs) is modulated by receptors for the Fc region of IgG (FcγRs), and alterations in their affinity or function have been associated with risk of autoimmune diseases, including systemic lupus erythematosus (SLE). The low-affinity FcγR 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 × 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 FcγRIIB (I232T) which abolishes inhibitory function, both reduced CN of FCGR3B and homozygosity of the FcγRIIB-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 FcγRs must be made in the context of LD involving CNV regions.
doi:10.1093/hmg/ddq216
PMCID: PMC2908468  PMID: 20508037
8.  Importing ArrayExpress datasets into R/Bioconductor 
Bioinformatics  2009;25(16):2092-2094.
Summary:ArrayExpress is one of the largest public repositories of microarray datasets. R/Bioconductor provides a comprehensive suite of microarray analysis and integrative bioinformatics software. However, easy ways for importing datasets from ArrayExpress into R/Bioconductor have been lacking. Here, we present such a tool that is suitable for both interactive and automated use.
Availability: The ArrayExpress package is available from the Bioconductor project at http://www.bioconductor.org. A users guide and examples are provided with the package.
Contact: audrey@ebi.ac.uk
Supplementary information:Supplementary data are available Bioinformatics online.
doi:10.1093/bioinformatics/btp354
PMCID: PMC2723004  PMID: 19505942
9.  ArrayExpress update—from an archive of functional genomics experiments to the atlas of gene expression 
Nucleic Acids Research  2008;37(Database issue):D868-D872.
ArrayExpress http://www.ebi.ac.uk/arrayexpress consists of three components: the ArrayExpress Repository—a public archive of functional genomics experiments and supporting data, the ArrayExpress Warehouse—a database of gene expression profiles and other bio-measurements and the ArrayExpress Atlas—a new summary database and meta-analytical tool of ranked gene expression across multiple experiments and different biological conditions. The Repository contains data from over 6000 experiments comprising approximately 200 000 assays, and the database doubles in size every 15 months. The majority of the data are array based, but other data types are included, most recently—ultra high-throughput sequencing transcriptomics and epigenetic data. The Warehouse and Atlas allow users to query for differentially expressed genes by gene names and properties, experimental conditions and sample properties, or a combination of both. In this update, we describe the ArrayExpress developments over the last two years.
doi:10.1093/nar/gkn889
PMCID: PMC2686529  PMID: 19015125
10.  MAGETabulator, a suite of tools to support the microarray data format MAGE-TAB 
Bioinformatics  2008;25(2):279-280.
Summary: The MAGE-TAB format for microarray data representation and exchange has been proposed by the microarray community to replace the more complex MAGE-ML format. We present a suite of tools to support MAGE-TAB generation and validation, conversion between existing formats for data exchange, visualization of the experiment designs encoded by MAGE-TAB documents and the mining of such documents for semantic content.
Availability: Software is available from http://tab2mage.sourceforge.net/
Contact: tfrayner@gmail.com
doi:10.1093/bioinformatics/btn617
PMCID: PMC2638998  PMID: 19038988
11.  A simple spreadsheet-based, MIAME-supportive format for microarray data: MAGE-TAB 
BMC Bioinformatics  2006;7:489.
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.
doi:10.1186/1471-2105-7-489
PMCID: PMC1687205  PMID: 17087822

Results 1-11 (11)