A nested comparison allows you to determine which genes respond differently to a treatment condition, respective to some other metadata.
For example, consider the design of one example data where cells with and without an ER were measured at 10hrs and at 48 hrs. The goal is to find the genes that respond differently over time in the ER vs. noER cells, you would perform a nested comparison.
First, compare ER10-ER48 to find the genes that are differentially expressed in cells with an ER (ERgenes). Next, compare noER10-noER48 to find the genes differentially expressed in cells with no ER (noERgenes). Finally, to find the genes that respond differently over time in ER vs. noER cells, compare DE ERgenes with DE noERgenes, that is: (ER10 - ER48) - (noER10 - noER48)
Selecting “Interaction only” will return significant results from only the last contrast. Otherwise the full model is returned, which is the combination of significant genes from all three contrasts described above.