ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

生物 室管膜瘤 染色质免疫沉淀 遗传学 染色质 表观遗传学 基因 癌症研究 细胞生物学 计算生物学 基因表达 DNA甲基化 发起人 病理 医学
作者
Amir Arabzade,Yanhua Zhao,Srinidhi Varadharajan,Hsiao‐Chi Chen,Selin Jessa,Bryan Rivas,Austin J. Stuckert,Minerva Solis,Alisha Kardian,Dana Tlais,Brian Golbourn,Ann-Catherine J. Stanton,Yuen San Chan,Heike Brötz‐Oesterhelt,Kristen L. Karlin,Kathleen Kong,Robert Kupp,Baoli Hu,Sarah G. Injac,Madeline Ngo
出处
期刊:Cancer Discovery [American Association for Cancer Research]
卷期号:11 (9): 2200-2215 被引量:84
标识
DOI:10.1158/2159-8290.cd-20-1066
摘要

Abstract More than 60% of supratentorial ependymomas harbor a ZFTA–RELA (ZRfus) gene fusion (formerly C11orf95–RELA). To study the biology of ZRfus, we developed an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZRfus tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZRfus-driven ependymoma. In addition to direct canonical NFκB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with PLAGL family transcription factor (TF) motifs. ZRfus activates gene expression programs through recruitment of transcriptional coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by PLAGL TF proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks. Significance: Ependymomas are aggressive brain tumors. Although drivers of supratentorial ependymoma (ZFTA- and YAP1-associated gene fusions) have been discovered, their functions remain unclear. Our study investigates the biology of ZFTA–RELA-driven ependymoma, specifically mechanisms of transcriptional deregulation and direct downstream gene networks that may be leveraged for potential therapeutic testing. This article is highlighted in the In This Issue feature, p. 2113
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