RESUMEN
MOTIVATION: As the number of studies looking at differences between DNA methylation increases, there is a growing demand to develop and benchmark statistical methods to analyse these data. To date no objective approach for the comparison of these methods has been developed and as such it remains difficult to assess which analysis tool is most appropriate for a given experiment. As a result, there is an unmet need for a DNA methylation data simulator that can accurately reproduce a wide range of experimental setups, and can be routinely used to compare the performance of different statistical models. RESULTS: We have developed WGBSSuite, a flexible stochastic simulation tool that generates single-base resolution DNA methylation data genome-wide. Several simulator parameters can be derived directly from real datasets provided by the user in order to mimic real case scenarios. Thus, it is possible to choose the most appropriate statistical analysis tool for a given simulated design. To show the usefulness of our simulator, we also report a benchmark of commonly used methods for differential methylation analysis. AVAILABILITY AND IMPLEMENTATION: WGBS code and documentation are available under GNU licence at http://www.wgbssuite.org.uk/ CONTACT: : owen.rackham@imperial.ac.uk or l.bottolo@imperial.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Asunto(s)
Benchmarking , Simulación por Computador , Metilación de ADN , Modelos Estadísticos , Análisis de Secuencia de ADN/métodos , Programas Informáticos , Sulfitos/química , Genoma Humano , Humanos , Procesos EstocásticosRESUMEN
Macrophages can fuse to form osteoclasts in bone or multinucleate giant cells (MGCs) as part of the immune response. We use a systems genetics approach in rat macrophages to unravel their genetic determinants of multinucleation and investigate their role in both bone homeostasis and inflammatory disease. We identify a trans-regulated gene network associated with macrophage multinucleation and Kcnn4 as being the most significantly trans-regulated gene in the network and induced at the onset of fusion. Kcnn4 is required for osteoclast and MGC formation in rodents and humans. Genetic deletion of Kcnn4 reduces macrophage multinucleation through modulation of Ca(2+) signaling, increases bone mass, and improves clinical outcome in arthritis. Pharmacological blockade of Kcnn4 reduces experimental glomerulonephritis. Our data implicate Kcnn4 in macrophage multinucleation, identifying it as a potential therapeutic target for inhibition of bone resorption and chronic inflammation.