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bioRxiv · 10.1101/2023.10.11.561932

Mapping chromatin state and transcriptional response in CIC-DUX4 undifferentiated round cell sarcoma

Thomas, N.·Luck, C.·Shlimon, N.·Kriska Ponce, R.·Kosibaty, Z.·Okimoto, R.
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Abstract

CIC-DUX4 is a rare and understudied transcription factor fusion oncoprotein. CIC-DUX4 co-opts native gene targets to drive a lethal form of human sarcoma. The molecular underpinnings that lead to oncogenic reprograming and CIC-DUX4 sarcomagenesis remain largely undefined. Through an integrative ChIP and RNA-Seq analysis using patient-derived CIC-DUX4 cells, we define CIC-DUX4 mediated chromatin states and function. We show that CIC-DUX4 primarily localizes to proximal and distal cis-regulatory elements where it associates with active histone marks. Our findings nominate key signaling pathways and molecular targets that enable CIC-DUX4 to mediate tumor cell survival. Collectively, our data demonstrate how the CIC-DUX4 fusion oncoprotein impacts chromatin state and transcriptional responses to drive an oncogenic program in undifferentiated sarcoma. SignificanceCIC-DUX4 sarcoma is a rare and lethal sarcoma that affects children, adolescent young adults, and adults. CIC-DUX4 sarcoma is associated with rapid metastatic dissemination and relative insensitivity to chemotherapy. There are no current standard-of-care therapies for CIC-DUX4 sarcoma leading to universally poor outcomes for patients. Through a deep mechanistic understanding of how the CIC-DUX4 fusion oncoprotein reprograms chromatin state and function, we aim to improve outcomes for CIC-DUX4 patients.

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Thomas, N., Luck, C., Shlimon, N., Kriska Ponce, R., Kosibaty, Z., Okimoto, R.. 2023-10-12. Mapping chromatin state and transcriptional response in CIC-DUX4 undifferentiated round cell sarcoma. https://doi.org/10.1101/2023.10.11.561932

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