Supporting our hypothesis that c-secretase has a role in multiple transcriptional regulatory activities, the GO cluster of ''transcription regulator activity'' is overrepresented through both its subclusters ''transcriptional activator activity'' GO0016563 and ''transcriptional repressor activity'' GO 0016564 (Fig. 2 , red boxes. Single member genes of each cluster are annotated in Supplemental Material Dataset S3). A well-described gene within the activator cluster is b-catenin (CTNNB1, FC = 3, p = 0.001), whereas an example of a gene in the cluster of ''transcriptional repressor activity'' is HES1. Hes1 (FC = 5.4, p = 7.69E-04) is a transcription factor that has previously been reported as a downstream target of the Notch signaling pathway [25] (Fig. 1) .