Biological Use Case: Extend knowledge about binding partners of a protein of your choice. In this case, the protein BDNF having a role in neurotrophic disease.
Interacting with the MiMi database
This mechanism is a Discovery approach starting from a single protein of interest to explore other possible protein interactions. We will show how to use the Mimi plugin for Cytoscape to retrieve protein interactions, and to visually display them. We will highlight certain features of the Mimi plugin.
- Bring up Cytoscape window, preloaded with TCF7L2.
- Input the search parameters for a single gene and file.
- Show the text panel for nodes. Press Ctrl+A to select all nodes. Open the text panel and select Description, Gene, Other Gene Names, process, function and Pathways. The columns can be switched and sorted on.
- SAGA, a subgraph approximate matching tool, can also be used with Cytoscape. Select all nodes (Ctrl+Alt+A). Right-click and select SAGA. Show the scoring and matches between the submitted network and the KEGG Matching pathways. Blue lines represent matching relationships, while red lines represent matching proteins.
- This links to the annotated KEGG Pathway. Click on the Link to KEGG Picture at the top of the match. Show how the matches to your submitted align to this picture.
- All nodes and edges should be selected when you return to the Cytoscape window. For an edge information description, Click on the Edge Attribute tab at the bottom and choose attributes: Genename, Provenance and Type.
- The Mimi provenance is visible through the browser.
- You can also integrate the parsed PubMed abstract literature data (bioNLP), and connect out to pubmed for the abstract information if needed. Returning to a single edge, select PARP1 and TCF7L2 edge and right-click to get BioNLP data.
- To launch the MimiWeb browser tool directly from the Cytoscape nodes, return to Cytoscape and couble click a single node CTNNB1 to launch MimiWeb.
Searching on the Mimi Web browser
From the browser, you can search by Concept of by individual protein.
- Open the MiMiWeb initial search page (preset blank page).
- Search for Neurotrophic.
- From this page, you can see interactions, literature references, launch Cytoscape or Gene2Mesh, directly from line. Click in BDNF to see summary page.
Different ways to look at protein-protein interactions and relationships
From a single protein summary page, we look at the protein interactions, and using the integrated tools, we can examine several different ways to look at protein protein interactions and relationships.
Gene Interaction Network
This is a NLP only summarization of the literature and tagged sentences which identify protein-protein interaction. Click on GIN.
This tool uses the term you are searching to initiate a PubMed search which will organize the output order to focus on search criteria being used. The MiSearch tool is organized and displayed based on your other search criteria (profile of search pattern). You can refine your search by adding authors, and this can link directly to Gene2Mesh, through mesh terms. Click on Brain Derived Neurotrophic Factor.
All PubMed abstracts were tagged for genes, and curated mesh terms associated with that abstract. An analysis of this reveals genes which are associated with Mesh Terms and vice versa. Fischer's exact text was used to rank order those genes most highly correlated with mesh headings, relative to how the gene is associate with other mesh terms. Gene2Mesh is now sorted on all genes tagged (scored) as being in articles with the mesh heading above. To pivot this search, click on a gene (BDNF) and show what other mesh headings are associated with that gene. These are searchable from the MiMi summary pages as well.
Additionally from the MiMi summary page we can look into MiMi itself and display the nearest neighbors to a protein using a Network Browser designed using FLASH technology. It is a portable alternative to Cytoscape. Back on the Mimi summary page for BDNF, click on NetBrowser. This shows a small network of genes (from MiMi) which interact with BDNF.
Searching from a literature term
As a different view into protein-protein interaction, we can start a search from a literature term rather than a protein. BioSearch2D was recently developed, and it uses a search term to identify all the abstracts in PubMed that are related, and extracts both Mesh Terms and Gene IDs from the literature search. This is displayed in a 2 dimensional co-occurence HeatMap. We can search for genes, highlight subsets of the map, and since our tools are all designed to be integrated, we can identify a small region of interest and ask what pathways are in that area by sending this list of genes to SAGA, and siaplying them in the FLASH Network Browser.
- Launch Biosearch2D.
- Enter search term Prostate Cancer Epigenetics.
- Search for EZH2 and highlight a small region for export. You can export to show literature and gene lists, as well as to Excel.
- Send the network to Mimi Gene Browser.
The Network Browser has some advanced features which we have just recently developed and will be expanded more. You can add or remove modes (based on MiMi protein-protein interaction), and further interact with SAGA in this tool as well.
- Go to Plugins->Manage Plugins->Available for Download->Network and Attribute I/O->MiMI. This will install the MiMI plugin for your use in Cytoscape.
- Go back to Plugins->MiMI Plugin->Query. A Query MiMI dialog box will pop up.
- Type your gene name into the box. For this example, use CSF1R.
- Press Search. MiMI will create a network for your gene, displaying the gene, receptors, and the genes that interact.
- You can change the layout by going to Layout->Cytoscape Layouts->Hierarchical Layout. This will show CSF1 as the central node.
- You can also expand the network to see the interactions of other genes in the network. Double click whichever gene you want to expand on.
- To find additional information on specific genes, Right-click on that gene and select MiMI Plugin->LinkOut NCIBI->MiMI Web. This will take you to the Michigan Molecular Interactions website to provide you with additional information on the gene, annotations on its function, and a list of the different genes it interacts with, including specific interaction details. The website will also provide you with sources and publications to reference, and links out to the National Center for Biology Information and PubMed.
Creating a Larger Network
- Go to Plugins->MiMI Plugin->Query.
- In the What to retrieve... drop menu, select 3. Query genes + neighbors' neighbors (It may take several minutes for a long gene list.
- Enter CSF1R into the box. Press Search. This will create a network of neighbors and second neighbors, but will take more time because the plugin is retrieving more information.
- You can analyze this using the MCODE plugin. Go to Plugins->MCODE->Start MCODE. Press Analyze. This will find densely connected subgraphs within the network, and will create a list of the subgraphs of densely connected gene sets.
- Click on one of the networks. In the Data Panel, hit the Select Attributes button . Here, you can select different features and information to display.
- You can create a separate network by clicking Create Sub-Network, which allows you to examine the network in more detail.
A video of this tutorial is available on YouTube through the following link: http://www.youtube.com/watch?v=R5yFOiRb18I