P300/CBP is an essential driver of pathogenic enhancer activity and gene expression in Ewing sarcoma

ABSTRACT: The t(11;22) translocation encodes the EWS::FLI1 fusion oncoprotein which is the primary driver of Ewing Sarcoma. EWS::FLI1 creates unique, de novo pathogenic enhancers that drive gene expression and are a central mechanism of oncogenesis. Which chromatin regulatory proteins are critical to this mechanism is understudied. Here, we perform a comparative analysis of the function of the chromatin complexes MLL3/4 and p300/CBP in EWS::FLI1 mediated gene regulation. Using EWS::FLI1 degradation models, we define a subset of EWS::FLI1-sensitive enhancers whose activity correlates with p300/CBP function. We perturb both chromatin complexes to establish that in contrast to MLL3/4, p300/CBP is a critical regulator of EWS::FLI1-driven enhancer activity and downstream gene expression. We also show tha

SUBMITTER: Laura, C Godfrey 

PROVIDER: S-SCDT-10_1038-S44319-025-00552-Z | biostudies-other |

REPOSITORIES: biostudies-other