Zfta–rela dictates oncogenic transcriptional programs to drive aggressive supratentorial ependymoma

Abstract

More than 60% of supratentorial ependymomas harbor a ZFTA–RELA (ZRfus ) gene fusion (formerly C11orf95–RELA). To study the biology of ZRfus, we devel-oped 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.