ZFTATranslocations Constitute Ependymoma Chromatin Remodeling and Transcription Factors

Abstract

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. Significance: 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

Cross-Species Genomics Reveals Oncogenic Dependencies in ZFTA/C11orf95 Fusion–Positive Supratentorial Ependymomas

“…S10A) (20) trimethylation and acetylation in our ZFTA fusion-driven mouse models corresponding well to respective levels in human tumors (Supplementary Fig. S10B-R) (20,21).…”

“…Based on our findings together with two co-submitted studies by Kupp et al. and Arabzade et al (20,21), C11orf95 has now been officially designated ZFTA (zinc finger translocation associated) by the HUGO Gene Nomenclature Committee.…”

“…In line with these findings, Kupp et al. observed that altering the Rel-homology domain in ZFTA-RELA fusions, which represents the DNA binding domain shared by the NF-κB family proteins for their signal transduction, did not result in loss of oncogenicity (21).…”

“…S9C-E), strongly suggesting other roles than nuclear shuttling of the shared ZF1 domain for tumorigenesis. Indeed, a co-submitted manuscript by Kupp et al demonstrates that chromatin binding and recruitment of chromatin remodeling complexes is related to the single ZF1 domain in ZFTA-RELA (21).…”

“…These findings suggest that additional oncogenic mechanisms are associated with the respective fusion partners. Importantly, this does not preclude an oncogenic role for the TAD within ZFTA-RELA and alternative fusion types, as Kupp et al demonstrated that the TAD of RELA contributes to the fusion-associated transcriptional program through recruitment of transcriptional co-regulators (21).…”