Use Case 3 - GREEKC

Use Case 3 HOW TO FIND FEEDBACK LOOP OF SPECIFIC TF

Biological question

For any Transcription Factors (TF), are there other TFs that can be involved in a direct feedback loop with that TF?

Feedback loops are important for many biological processes and general system’s behavior. The transcription factor NANOG is an important regulator in different biological processes, such as inner cell mass formation and embryonic stem cell proliferation, and self-renewal. Moreover, NANOG has been related to the general development of cancer, i.e. cell proliferation, epithelial-mesenchymal transition, apoptosis, and metastasis (PMID: 26618281). The regulation of this TF is of general interest, therefore we would like to find TFs which are regulated by Nanog and which themselves regulate Nanog, i.e. forming a feedback loop. Besides identifying the feedback loops, a more interesting question is whether the feedback loop is exerting negative or positive control.

SOLUTION

Use BioGateway Cytoscape Plugin to identify TFs that regulate NANOG by using the query builder of BioGateway.

This resource enables a Semantic Systems Biology approach and retrieves data that define relations among biological entities in the form of triples (using Resource Description Framework (RDF)).

To find possible feedback loops, the BioGateway Cytoscape Plugin can be used to display the interactions that lead to the regulation of NANOG. The search is done directly in the Query Builder of the BioGateway app.

The search is done directly in the Query Builder of the BioGateway app.

In the first line of the query, the NANOG human protein is selected as an entity, and “tfact2gene: involved in the regulation of” is chosen for the interaction with a “Set A”, which will return all the genes that are the transcriptional target of the transcription factor protein NANOG.
The next query line asks for all the proteins (Set B) that are encoded by the genes present in Set A.
The last line of the query asks for all the interactions from Set B (protein results) involved in the regulation of the NANOG gene.

Finally, all the query results can be imported into a new Network for graphical visualization.

RESULTS

The results show that 10 entities are related to the regulation of NANOG, forming independent positive feedback loops. These are:

ESRRB, SOX17, GATA6, FOXD3, POU5F1, NR0B1, GATA4, ZIC3, P53, ZNF281, and NANOG.

BioGateway query for NANOG interactions

Steps and results from the NANOG query in BioGateway Plugin in Cytoscape (version 3.8.2). In the BioGateway Query Builder the lines of the query are defined according to the above description (Step 1), and the query is run (Step 2). Then, the query results are selected and imported as a new network (Step 3). Finally, the layout style of the network can be change to get a better visualization of the results.

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