Fe65 protein interacts with the cytosolic domain of the amyloid precursor APP. Its possible involvement in gene regulation is suggested by numerous observations, including those demonstrating that it activates transcription. Here, we show that the Fe65 transcription activation domain overlaps with the WW domain of Fe65 and binds to the nucleosome assembly factor SET. This protein is required for the Fe65-mediated transactivation of a reporter gene. Two-step chromatin immunoprecipitation experiments demonstrate that a complex including Fe65/AICD/Tip60 and SET is associated with the KAI1 gene promoter. Suppression of SET levels by RNA interference shows that this protein is required for full levels of basal transcription of the KAI1 gene. These results further support the function of Fe65 and APP in gene regulation and show a new role for the SET factor.