%0 Journal Article
%A Kupp, Robert
%A Ruff, Lisa
%A Terranova, Sabrina
%A Nathan, Erica
%A Ballereau, Stephane
%A Stark, Rory
%A Sekhar Reddy Chilamakuri, Chandra
%A Hoffmann, Nadin
%A Wickham-Rahrmann, Katherine
%A Widdess, Marcus
%A Arabzade, Amir
%A Zhao, Yanhua
%A Varadharajan, Srinidhi
%A Zheng, Tuyu
%A Murugesan, Mohankumar K
%A Pfister, Stefan
%A Kawauchi, Daisuke
%A Pajtler, Kristian W
%A Deneen, Benjamin
%A Mack, Stephen C
%A Masih, Katherine E
%A Gryder, Berkley E
%A Khan, Javed
%A Gilbertson, Richard J
%T ZFTA-translocations constitute ependymoma chromatin remodeling and transcription factors.
%J Cancer discovery
%V 11
%N 9
%@ 2159-8290
%C Philadelphia, Pa.
%M DKFZ-2021-00678
%P 2216-2229
%D 2021
%Z 2021 Sep;11(9):2216-2229
%X ZFTA (C11orf95)-a gene of unknown function-partners with a variety of transcriptional co-activators in translocations that drive supratentorial ependymoma, a frequently lethal brain tumor. Understanding the function of ZFTA is key to developing therapies that inhibit these fusion proteins. Here, using a combination of transcriptomics, chromatin immunoprecipitation-sequencing, and proteomics, we interrogated a series of deletion-mutant genes to identify a tri-partite transformation mechanism of ZFTA-containing fusions, including: spontaneous nuclear translocation, extensive chromatin binding, and SWI/SNF, SAGA and NuA4/Tip60 HAT chromatin modifier complex recruitment. Thereby, ZFTA tethers fusion proteins across the genome, modifying chromatin to an active state, and enabling its partner transcriptional co-activators to promote promiscuous expression of a transforming transcriptome. Using mouse models, we validate further those elements of ZFTA-fusion proteins that are critical for transformation-including ZFTA zinc fingers and partner gene transactivation domains-thereby unmasking vulnerabilities for therapeutic targeting.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:33741711
%R 10.1158/2159-8290.CD-20-1052
%U https://inrepo02.dkfz.de/record/168090