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May 21st, 2025
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Nationwide Children\\\'s Hospital, Center for Childhood Cancer Research, Columbus, OH 43205, USA
genomics
biorxiv

Fusion transcription factor dosage controls cell state in rhabdomyosarcoma

Hoffman, R. A.Open in Google Scholar•Wang, M.Open in Google Scholar•Sunkel, B. D.Open in Google Scholar•Nguyen, T. H.Open in Google Scholar•Lopez-Nava, J.Open in Google Scholar•Chatterjee, B.Open in Google Scholar•Sun, W.Open in Google Scholar•Barr, F. G.Open in Google Scholar•Stanton, B. Z.Open in Google Scholar

In the fusion-positive subset of rhabdomyosarcoma, the PAX3::FOXO1 oncoprotein is the most common fusion driver. We previously established a human myoblast system for inducible expression of PAX3::FOXO1. In the current study, we modulate PAX3::FOXO1 protein expression to understand the epigenetic and phenotypic functions at different PAX3::FOXO1 levels. Proliferative and oncogenic outcomes depend on PAX3::FOXO1 dosage in this system with transformation dominant at intermediate levels and growth suppression dominant at high levels. After prolonged PAX3::FOXO1 expression, there is dosage-dependent heterogeneity in single cell gene expression profiles. We observe a dosage-specific effect for PAX3::FOXO1 chromatin recognition and identify factors that modulate PAX3::FOXO1 chromatin binding. PAX3::FOXO1 dosage affects expression signatures related to cell cycle, epithelial-mesenchymal transition, and myogenesis. Whereas intermediate PAX3::FOXO1 expression maximizes chromatin binding to modulate gene expression, high PAX3::FOXO1 expression alters S phase progression and increases accessibility behind the replication fork. We conclude that PAX3::FOXO1 exerts dosage-dependent functions to influence epigenetic heterogeneity in fusion-positive rhabdomyosarcoma.

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