Although many gene set enrichment analysis methods have been proposed to explore associations between a phenotype and a group of genes sharing common biological functions or involved in the same biological process, the underlying biological mechanisms of identified gene sets are typically unexplained. To overcome this limitation, we propose a method called DRAGEN (Differential Regulation based enrichment Analysis for GENe sets) to identify gene sets in which a significant proportion of genes have their transcriptional regulatory patterns changed in a perturbed phenotype.