The Exp3 project develops an iterative approach for exploring and explaining expression patterns in regulatory networks using targeted combinatorial perturbations (multiple siRNA knockouts/ knockdowns) of genes and sets of genes followed by the subsequent gene and protein expression measurements of the perturbed system. Causal, time and space resolved executable (Petri Nets with Fuzzy Logic = PNFL) models are derived and exploited for the prediction of new target sets and new perturbations.

This Exp3 systems approach is applied for the investigation of Herpes virus infections to identify relevant virus host factors and allows for investigating specific innate and adaptive immune response pathways challenged by Herpes viruses in a much more in-depth way as previously possible. Moreover, we consider the combinatorial regulatory effects of (Herpes viral) miRNAs and siRNA and their effect on protein isoforms and their structures.

The proposed approach is applicable to a wide range of systems modeling problems by drastically reducing the number of experiments yielding much more focused experimental data for obtaining causal models. As the approach is predictive it will also allow for proposing validation experiments, which can be performed via the very same protocol. The Exp3 method should save time and money in discovering new regulatory mechanisms.

 

Prof. Dr. Dr. Jürgen Haas

University of Edinburgh, UK, and Max-von-Pettenkofer-Institute, Ludwig-Maximilians-Universit Munich

 

Prof. Dr. Eckart Wolf

Gene Center, Ludwig-Maximilians-University Munich

 

Birzele, F., G. Csaba and R. Zimmer (2008). "Alternative splicing and protein structure evolution." Nucleic Acids Res 36(2): 550-8.

 

Csaba, G. (2008). syngrep. Personal Communication. Munich.

Csaba, G., E. Berchtold, et al. (2012). RelExplain - Gene Set Enrichment using Significant Area Search on mined Regulatory Relation network. submitted.

 

Csaba, G., S. Wolf, et al. (2012). SynTree: a fast context-dependent and ontology-based NER method and its application to psychiatric disorders. submitted.

 

Dölken, L., G. Malterer, et al. (2010). "Systemic Analysis of Viral and Cellular miRNA Targets in Cells Latently Infected with Human gamma-Herpesviruses through RISC Immunoprecipitation Assays." Cell Host & Microbe 7(4): 324-334.

 

Dölken, L., Z. Ruzsics, et al. (2008). "High-resolution gene expression profiling for simultaneous kinetic parameter analysis of RNA synthesis and decay." RNA 14(9): 1959-1972.

Erhard, F., L. H. Gregersen, et al. (2012). RIP-chip enrichment analysis. European Conference on Computational Biology (ECCB2012). Basel, Switzerland. submitted.

 

Fischer, W., L. Windhager, et al. (2010). "Strain-specific genes of Helicobacter pylori: genome evolution driven by a novel type IV secretion system and genomic island transfer." Nucleic Acids Res 38(18): 6089-6101.

 

Fossum, E., C. C. Friedel, et al. (2009). "Evolutionarily conserved herpesviral protein interaction networks." PLoS Pathogens 5(9): e1000570.

 

Friedel, C. C. and L. Dolken (2009). "Metabolic tagging and purification of nascent RNA: implications for transcriptomics." Mol Biosyst 5(11): 1271-1278.

 

Friedel, C. C., L. Dolken, et al. (2009). "Conserved principles of mammalian transcriptional regulation revealed by RNA half-life." Nucleic Acids Res 37(17): e115.

 

Friedel, C. C. and J. Haas (2011). "Virus-host interactomes and global models of virus-infected cells." Trends in Microbiology 19(10): 501-508.

 

Friedel, C. C., S. Kaufmann, et al. (2010). "HALO--a Java framework for precise transcript half-life determination." Bioinformatics 26(9): 1264-1266.

 

Friedel, C. C. and R. Zimmer (2006). "Toward the complete interactome." Nature Biotechnology 24(6): 614-615.

 

Fundel, K., D. Guettler, et al. (2004). Exact versus approximate string matching for protein name identification. BioCreative Challenge Evaluation Workshop, Granada, Spain.

 

Fundel, K., D. Guttler, et al. (2005). "A simple approach for protein name identification: prospects and limits." BMC Bioinformatics 6 Suppl 1: S15.

 

Fundel, K., R. Kuffner, et al. (2007). "RelEx--relation extraction using dependency parse trees." Bioinformatics 23(3): 365-371.

Fundel, K. and R. Zimmer (2006). "Gene and protein nomenclature in public databases." BMC Bioinformatics 7: 372.

 

Fundel, K. and R. Zimmer (2007). Human Gene Normalization by an Integrated Approach including Abbreviation Resolution and Disambiguation. Second BioCreative Challenge Evaluation Workshop. A. Valencia. Madrid, Spain.

Geistlinger, L., G. Csaba, R. Küffner, N. Mulder, and R. Zimmer. From Sets to Graphs: Towards a Realistic Enrichment Analysis of Transcriptomic Systems. Bioinformatics, vol 27, no. 13, pp. i366-i373, 2011.

 

Gonzalez, O., S. Gronau, F. Pfeiffer, E. Mendoza, R. Zimmer and D. Oesterhelt (2009). "Systems analysis of bioenergetics and growth of the extreme halophile Halobacterium salinarum." PLoS Computational Biology 5(4): e1000332.

 

Hanisch, D., J. Fluck, et al. (2003). "Playing biology's name game: identifying protein names in scientific text." Pac Symp Biocomput: 403-414.

 

Hanisch, D., K. Fundel, et al. (2004). ProMiner: Organism-specific protein name detection using approximate string matching. BioCreative Challenge Evaluation Workshop, Granada, Spain.

 

Hanisch, D., K. Fundel, et al. (2005). "ProMiner: rule-based protein and gene entity recognition." BMC Bioinformatics 6 Suppl 1: S14.

 

Küffner, R., Tobias Petri, Lukas Windhager, Ralf Zimmer. Petri Nets with Fuzzy Logic (PNFL): Reverse Engineering and Parametrization. PLoS One, vol 5, pp. e12807, 09 2010.

Naeem, H., R. Küffner, G. Csaba and R. Zimmer (2010). "miRSel: automated extraction of associations between microRNAs and genes from the biomedical literature." BMC Bioinformatics. 11: 135.

 

Petri, T., E. Berchtold, et al. (2011). "Detection and correction of probe-level measurement artifacts." Manuscript.

 

Pfefferle, S., J. Schopf, et al. (2011). "The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors." PLoS Pathogens 7(10): e1002331.

 

Sorg, D., K. Danowski, et al. (2012). "The immune response of primary bovine mammary epithelial cells to an in vitro mastitis challenge measured with microfluidic high-throughput RT-qPCR." Biotechnology letters submitted.

 

Uetz, P., Y. A. Dong, et al. (2006). "Herpesviral protein networks and their interaction with the human proteome." Science 311(5758): 239-242.

 

Uetz, P., S. V. Rajagopala, et al. (2004). "From ORFeomes to protein interaction maps in viruses." Genome Res 14(10B): 2029-2033.

 

von Brunn, A., C. Teepe, et al. (2007). "Analysis of intraviral protein-protein interactions of the SARS coronavirus ORFeome." PLoS ONE 2(5): e459.

 

Windhager, L., T. Bonfert, et al. (2012). "Ultra short and progressive 4sU-tagging reveals key characteristics of RNA processing at nucleotide resolution." Genome Research in press.