Download - NetBioSIG2013-Talk Martina Kutmon
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Building Regulatory Networks with CyTargetLinker
Martina [email protected]
NetBio SIG: July 19, 2013
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Outline
• Background
• CyTargetLinker walkthrough
• Biological applications
• Next steps
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Background
• Our initial use case: biological pathways
o Graphical representation of a biological processo Intuitiveo Signaling pathways, metabolic pathwayso Contains gene products, proteins, metabolites,
different reactions and interactions
o WikiPathways, Reactome, KEGG, ...
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Background
http://wikipathways.org/index.php/Pathway:WP197
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Background
• Regulatory elements are often missing in pathways
o transcription factorso microRNAso drugso ...
• Why?o Is the specific regulator really involved in this pathway?o Often it makes the pathway to big and cluttered.
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Basic Idea
microRNA
miRecords database
miRTarBase database
TFe database
transcription factor
target gene
proteins/existing network
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Goal
• Integration of regulatory elements in network analysis
• Using multiple datasources in parallel
• Flexibility and extensibility
• Different regulatory interactions, e.g. TF-target or miRNA-target
• Integrate functionality in the Cytoscape framework
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Goal
User-friendly for biologists and bioinformaticians
Development of a Cytoscape app to integrate regulatory interactions into network analysis
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Cytoscape app CyTargetLinkerprojects.bigcat.unimaas.nl/cytargetlinker
CyTargetLinker Walkthrough
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Where does the data come from?
• Regulatory interactions are loaded from RINs
o RIN = Regulatory Interaction Networks
o RINs support multiple identifier systems (BridgeDb)o Existing regulatory interaction databases or user
generatedo Conversion scripts are open source and available on
github o RINs for different species and interaction types are
available on the CyTargetLinker website
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RINs
http://mirtarbase.mbc.nctu.edu.tw
XGMML file with microRNA -> gene interactions from miRTarBase 3.5
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CyTargetLinker workflow
Initial network
Protein-protein network, biological pathway, single nodes, ...
Gene set from MSigDBGNF2_MKI67 - cancer gene neighborhoods
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CyTargetLinker workflow
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CyTargetLinker workflow
Extension of the initial network with microRNA-target information
predicted and validated miRNA targets from 4 different resources
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CyTargetLinker workflow
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CyTargetLinker workflow
Show/Hide functionalityonly interactions from validated resources are shown
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CyTargetLinker workflow
only interactions supported by at least two resources are shown
Overlap threshold functionality
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CyTargetLinker workflow
• CyTargetLinker extracts the regulatory interactions from all RINs relevant for the initial network
• CyTargetLinker for Cytoscape 3 in pre-release status (downloadable from website)
• CyTargetLinker for Cytoscape 2.8 can be installed through the plugin manager
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Biological Applications
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microRNAs in breast cancer
199 interactions from miRecords443 interactions from miRTarBase
Heneghan, H. M., et al. "MicroRNAs as novel biomarkers for breast cancer."Journal of oncology 2010 (2009).
BCL2 --> target of 4 miRNAsCDKN1A --> target of 4 miRNAsRB1 --> target of 2 miRNAsERBB2 --> target of 2 miRNAs...
Identify target genes of specific miRNAs and start building hypotheses
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Pathway Extension
ENCODE: the Encyclopedia Of DNA Elements
•Goal: identify all functional elements in the human genome sequence
•Paper: Architecture of the human regulatory network derived from ENCODE data --> proximal and distal transcription factor regulation
•Data is provided as networks
•RINs are provided on the website
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Pathway Extension
DNA damage response pathway
127 proximal interactions (blue)82 distal interactions (red)
BRCA1 - distal regulationABL1 - proximal regulation
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Next steps
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Next steps
• Conversion of more resources to RINs
• Data retrieval through other services (webservices, RDF, Neo4j databases)
• Export function to show which interactions were added in which extension step
• Statistical output - VENN diagram showing overlapping interactions
• Improved result visualization options (shape and color of added nodes)
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Summary
• User-friendly Cytoscape app to integrate regulatory interactions into network analysis in a flexible and extensible way
• RINs and tutorials can be found on http://projects.bigcat.unimaas.nl/cytargetlinker
• CyTargetLinker is Open Source:o http://github.com/mkutmon/cytargetlinkero http://github.com/mkutmon/rin-creation
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Acknowledgements
• Thomas Kelder
• Susan Coort
• Chris Evelo
Students:
• Pooja Mandaviya
• Naïme Douallin
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Thank you for your attention!Questions?