American Association for Cancer Research
21598290cd201052-sup-247465_2_supp_6953503_qp8r71.pdf (163.7 kB)

Figure S5 from ZFTA Translocations Constitute Ependymoma Chromatin Remodeling and Transcription Factors

Download (163.7 kB)
journal contribution
posted on 2023-04-03, 23:42 authored by Robert Kupp, Lisa Ruff, Sabrina Terranova, Erica Nathan, Stephane Ballereau, Rory Stark, Chandra Sekhar Reddy Chilamakuri, Nadin Hoffmann, Katherine Wickham-Rahrmann, Marcus Widdess, Amir Arabzade, Yanhua Zhao, Srinidhi Varadharajan, Tuyu Zheng, Mohankumar Murugesan, Stefan M. Pfister, Daisuke Kawauchi, Kristian W. Pajtler, Benjamin Deneen, Stephen C. Mack, Katherine E. Masih, Berkley E. Gryder, Javed Khan, Richard J. Gilbertson

ZFTA-RELAFUS1 domain interactomes


Cancer Research UK

Brain Tumour Charity

Cancer Prevention and Research Institute of Texas




ZFTA (C11orf95)—a gene of unknown function—partners with a variety of transcriptional coactivators 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 tripartite 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 coactivators 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. Ependymomas are hard-to-treat brain tumors driven by translocations between ZFTA and a variety of transcriptional coactivators. We dissect the transforming mechanism of these fusion proteins and identify protein domains indispensable for tumorigenesis, thereby providing insights into the molecular basis of ependymoma tumorigenesis and vulnerabilities for therapeutic targeting.This article is highlighted in the In This Issue feature, p. 2113