p300/CBP is an essential driver of pathogenic enhancer activity and gene expression in Ewing sarcoma.

Laura C Godfrey; Brandon Regalado; Sydney R Schweber; Charles Hatton; Daniela V Wenge; Yanhe Wen; Meaghan Boileau; Maria Wessels; Jun Qi; Christopher J Ott; Kimberly Stegmaier; Miguel N Rivera; Scott A Armstrong

doi:10.1038/s44319-025-00552-z

PubMed · 40890402

p300/CBP is an essential driver of pathogenic enhancer activity and gene expression in Ewing sarcoma.

Laura C Godfrey·Brandon Regalado·Sydney R Schweber·Charles Hatton·Daniela V Wenge·Yanhe Wen·Meaghan Boileau·Maria Wessels·Jun Qi·Christopher J Ott·Kimberly Stegmaier·Miguel N Rivera·Scott A Armstrong

View original source ↗Export metadata ↓

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 that p300/CBP small-molecule inhibition decelerates tumor growth in vivo. Our work highlights the context-dependent nature of chromatin protein activity at oncogenic enhancers and reveals p300/CBP as an important regulator of Ewing sarcoma.

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Laura C Godfrey, Brandon Regalado, Sydney R Schweber, Charles Hatton, Daniela V Wenge, Yanhe Wen, Meaghan Boileau, Maria Wessels, Jun Qi, Christopher J Ott, Kimberly Stegmaier, Miguel N Rivera, Scott A Armstrong. 2025-09-01. p300/CBP is an essential driver of pathogenic enhancer activity and gene expression in Ewing sarcoma.. https://doi.org/10.1038/s44319-025-00552-z

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2026

EWS-RNA Binding Protein 1: Structural Insights into Ewing Sarcoma by Conformational Dynamics Investigations.

BACKGROUND: Prior research has demonstrated that proteins play a significant role in the prognosis and treatments of various sarcomas, including Ewing sarcoma through the interplay of downstream signaling cascades. However, there is limited understanding about the strcucture conformation of EWSR1 and its structural implication in the prognosis of Ewsing Sarcoma by interaction with RNA molecules. AIMS: The primary goal of ongoing research is to determine how EWSR1 contributes to Ewing sarcoma. OBJECTIVE: The current study explores the complexity of EWSR1 structure and its conformational interactions with RNA in relation to Ewing sarcoma. METHODS: Here, we employed a comparative modeling approach to predict EWSR1 domains separately and assembled them into one structural unit using a DEMO server. Additionally, the RNA motifs interacting with EWSR1 were predicted, and the 3D model was built using RNAComposer. Protein-RNA docking and MD simulation studies were carried out to check the intermolecular interactions and stability behavior of docked EWSR1-RNA complexes. RESULTS: The overall results explore the structural insights into EWSR1 and their interactions with RNA, which may play a momentous role in co- and post-transcriptional regulation to control gene expression. CONCLUSION: Taken togather, our findings suggest that EWSR1 may be a useful therapeutic target for the diagnosis and management of Ewing sarcoma.

Sarcoma, Ewing↗

PubMed2024

STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1.

Cohesin complexes carrying STAG1 or STAG2 organize the genome into chromatin loops. STAG2 loss-of-function mutations promote metastasis in Ewing sarcoma, a pediatric cancer driven by the fusion transcription factor EWS::FLI1. We integrated transcriptomic data from patients and cellular models to identify a STAG2-dependent gene signature associated with worse prognosis. Subsequent genomic profiling and high-resolution chromatin interaction data from Capture Hi-C indicated that cohesin-STAG2 facilitates communication between EWS::FLI1-bound long GGAA repeats, presumably acting as neoenhancers, and their target promoters. Changes in CTCF-dependent chromatin contacts involving signature genes, unrelated to EWS::FLI1 binding, were also identified. STAG1 is unable to compensate for STAG2 loss and chromatin-bound cohesin is severely decreased, while levels of the processivity factor NIPBL remain unchanged, likely affecting DNA looping dynamics. These results illuminate how STAG2 loss modifies the chromatin interactome of Ewing sarcoma cells and provide a list of potential biomarkers and therapeutic targets.