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Rhabdomyosarcoma fusion oncoprotein initially pioneers a neural signature in vivo

Jack Kucinski, Alexi Tallan, Cenny Taslim

    Biorxiv : the Preprint Server for Biology
    |July 29, 2024
    PubMed

    Insights

    Pediatric rhabdomyosarcoma is driven by PAX3::FOXO1, which pioneers inaccessible chromatin. This interaction activates neural gene programs, revealing a critical event in tumor initiation.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Developmental Biology

    Background:

    • Fusion-positive rhabdomyosarcoma is an aggressive pediatric cancer.
    • The PAX3::FOXO1 fusion protein is the primary genetic driver.
    • Current understanding of its in vivo epigenetic mechanisms is limited, hindering therapeutic development.

    Purpose of the Study:

    • To investigate how PAX3::FOXO1 interacts with chromatin in vivo.
    • To understand the epigenetic mechanisms and transcriptional consequences of PAX3::FOXO1 binding.
    • To identify potential therapeutic targets for rhabdomyosarcoma.

    Main Methods:

    • Established a PAX3::FOXO1 zebrafish injection model.
    • Developed a semi-automated ChIP-seq normalization strategy.
    • Analyzed PAX3::FOXO1 genome binding, chromatin accessibility, and H3K27ac redistribution.

    Main Results:

    • PAX3::FOXO1 pioneers inaccessible chromatin via partial/homeobox motif recognition.
    • PAX3::FOXO1 binding alters chromatin accessibility and redistributes H3K27ac.
    • Activated neural transcriptional programs and signatures were identified, mirroring clinical rhabdomyosarcoma profiles.

    Conclusions:

    • Partial/homeobox motif recognition is a novel mode of PAX3::FOXO1 pioneer function.
    • Neural signatures represent a critical PAX3::FOXO1-driven tumor initiation event.
    • Findings offer new insights into rhabdomyosarcoma pathogenesis and potential therapeutic strategies.

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