This Program Project is aimed at understanding the mechanisms that control growth and multicellular development in Dictyostelium. In the previous project period we took a functional genomics approach to high-throughput mutant phenotyping, transcriptional profiling, and computational modeling that allowed us to draw functional inferences for hundreds of genes. Over the next five years we will focus our efforts on understanding transcriptional control during development and bacterial recognition, both during the growth of solitary Dictyostelium amoebae and in the context of an innate immune response during their development. We will intersect transcriptional profiling data with physiological data to extract information about the genetic networks that coordinate bacterial recognition in Dictyostelium and characterize the genes and pathways involved. We will also test which regulators are responsible for the dramatic transcriptional changes that accompany Dictyostelium development. We will use RNA sequencing (RNA-seq) and Chromatin Immunoprecipitation (ChlP-seq) to identify genes that are directly regulated by these transcription factors. We will develop computational techniques and integrative data mining to infer gene function and to construct consensus gene network models for use as scaffolds upon which we can propose additional experiments and add layers of information from other experiments. We also propose to implement the new methods within modem server-based software architecture with visualization-rich interactive interfaces that will make the entire planned data analytics transparent and operable by biologists with no computer science background. This work will help establish the amoeba as a model system for the study of innate immunity, leading to the development of tools and techniques that can be applied to understanding the response of eukaryotic cells to bacteria. Our strains, data, and software will be freely available to the research community and well integrated with dictyBase, the primary Dictyostelium community resource and data warehouse.
The response of amoebae to bacteria is relevant to infections in humans because it likely involves conserved pathways used by eukaryotes to defend against bacteria. Using diverse, rich, high-quality data sets we will devise new computational methods to accurately infer gene function, equipping researchers with improved means to analyze their own biomedical data. The methods we develop can be applied to other systems, improving our ability to predict gene function in development and in disease.
|Cai, Huaqing; Katoh-Kurasawa, Mariko; Muramoto, Tetsuya et al. (2014) Nucleocytoplasmic shuttling of a GATA transcription factor functions as a development timer. Science 343:1249531|
|Zitnik, Marinka; Zupan, Blaž (2014) Gene network inference by probabilistic scoring of relationships from a factorized model of interactions. Bioinformatics 30:i246-i254|
|Zitnik, Marinka; Zupan, Blaz (2014) Matrix factorization-based data fusion for gene function prediction in baker's yeast and slime mold. Pac Symp Biocomput :400-11|
|Weirauch, Matthew T; Yang, Ally; Albu, Mihai et al. (2014) Determination and inference of eukaryotic transcription factor sequence specificity. Cell 158:1431-43|
|Miranda, Edward Roshan; Rot, Gregor; Toplak, Marko et al. (2013) Transcriptional profiling of Dictyostelium with RNA sequencing. Methods Mol Biol 983:139-71|
|Miranda, Edward Roshan; Zhuchenko, Olga; Toplak, Marko et al. (2013) ABC transporters in Dictyostelium discoideum development. PLoS One 8:e70040|
|Nasser, Waleed; Santhanam, Balaji; Miranda, Edward Roshan et al. (2013) Bacterial discrimination by dictyostelid amoebae reveals the complexity of ancient interspecies interactions. Curr Biol 23:862-72|
|Huang, Eryong; Talukder, Shaheynoor; Hughes, Timothy R et al. (2011) BzpF is a CREB-like transcription factor that regulates spore maturation and stability in Dictyostelium. Dev Biol 358:137-46|
|Sucgang, Richard; Kuo, Alan; Tian, Xiangjun et al. (2011) Comparative genomics of the social amoebae Dictyostelium discoideum and Dictyostelium purpureum. Genome Biol 12:R20|
|Loomis, William F; Shaulsky, Gad (2011) Developmental changes in transcriptional profiles. Dev Growth Differ 53:567-75|
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