How can a computationally determined three-way gene interaction be biologically validated? What kind of assays or tests must be performed using cell/tissue-based and/or mouse models to prove that the three genes may indeed have a joint effect?
Let's say, it is easier to identify and validate gene interactions that involve transcription factors like FOXM1. Consider a three-way gene interaction in Breast cancer - FOXM1-BUB1-CHEK1 - that can be tested for direct interactions via western blot and reporter assays. But such interactions may or may not be interesting - given the fact that transcription factors may be affecting expression levels of other genes. Most computational studies are focussed on identifying gene interactions based on coexpression or co-occurrence. There is literature on computationally identifying AND/OR relationships between interacting genes. I don't have a specific example to provide but, for argument sake, if we did suspect that three genes are interacting in an AND like manner, how do we biologically validate this finding? I'd also appreciate if you may have comments on the usefulness of such findings, particularly, with regard to designing more efficacious combination therapies against a disease".