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

More than 60% of supratentorial ependymomas harbor a <i>ZFTA-RELA</i> (ZR^fus) gene fusion (formerly <i>C11orf95-RELA</i>). To study the biology of ZR^fus, we developed an autochthonous mouse tumor model using <i>in utero</i> electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZR^fus tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZR^fus-driven ependymoma. In addition to direct canonical NFκB pathway activation, ZR^fus 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. ZR^fus activates gene expression programs through recruitment of transcriptional coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZR^fus 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 (<i>ZFTA</i>- and <i>YAP1</i>-associated gene fusions) have been discovered, their functions remain unclear. Our study investigates the biology of <i>ZFTA-RELA</i>-driven ependymoma, specifically mechanisms of transcriptional deregulation and direct downstream gene networks that may be leveraged for potential therapeutic testing.<i>This article is highlighted in the In This Issue feature, p. 2113</i>.