TY  - JOUR
AU  - Kupp, Robert
AU  - Ruff, Lisa
AU  - Terranova, Sabrina
AU  - Nathan, Erica
AU  - Ballereau, Stephane
AU  - Stark, Rory
AU  - Sekhar Reddy Chilamakuri, Chandra
AU  - Hoffmann, Nadin
AU  - Wickham-Rahrmann, Katherine
AU  - Widdess, Marcus
AU  - Arabzade, Amir
AU  - Zhao, Yanhua
AU  - Varadharajan, Srinidhi
AU  - Zheng, Tuyu
AU  - Murugesan, Mohankumar K
AU  - Pfister, Stefan
AU  - Kawauchi, Daisuke
AU  - Pajtler, Kristian W
AU  - Deneen, Benjamin
AU  - Mack, Stephen C
AU  - Masih, Katherine E
AU  - Gryder, Berkley E
AU  - Khan, Javed
AU  - Gilbertson, Richard J
TI  - ZFTA-translocations constitute ependymoma chromatin remodeling and transcription factors.
JO  - Cancer discovery
VL  - 11
IS  - 9
SN  - 2159-8290
CY  - Philadelphia, Pa.
M1  - DKFZ-2021-00678
SP  - 2216-2229
PY  - 2021
N1  - 2021 Sep;11(9):2216-2229
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:33741711
DO  - DOI:10.1158/2159-8290.CD-20-1052
UR  - https://inrepo02.dkfz.de/record/168090
ER  -