Publication Date

9-1-2021

Journal

Cancer Discovery

DOI

10.1158/2159-8290.CD-20-1066

PMID

33741710

PMCID

PMC8418998

PubMedCentral® Posted Date

3-1-2022

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, DNA-Binding Proteins, Disease Models, Animal, Ependymoma, Mice, Supratentorial Neoplasms, Transcription Factor RelA, Transcription Factors

Abstract

Over 60% of supratentorial (ST) 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, ChIP, ATAC, and RNA sequencing and compared to human ZRfus driven ependymoma. In addition to direct canonical NF-κB 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 co-activators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by Plagl transcription factor proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks.

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