PAX3-FOXO1 Directed Transcriptional Activation is Mediated by PAX3 and FOXO1 Recognition Sequences

Alveolar Rhabdomyosarcoma (ARMS) patients carrying a chromosomal translocation of PAX3 and FOXO1 have the highest mortality rates, indicating the importance of understanding how this transcription factor influences gene expression. A search of an updated ChIP-seq screen of 3881 PAX3-FOXO1 putative binding sites revealed that 36% contained both a PAX3 paired domain and FOXO1 recognition sequence within close proximity. These data along with in vitro studies with several known and putative PAX3-FOXO1 targets suggest that both the PAX3 and FOXO1 DNA-binding domains mediate interactions with DNA. In addition, mutation of either the FOXO1 element or amino acids in the FOXO1 DNA-binding domain result in decreased PAX3-FOXO1 directed transcriptional activation. However, there exist many sequence variations within these putative binding sites, representing a need to perform further investigations to identify the sequence limitations of the PAX3-FOXO1 interaction. We are also interested in the biological environme...