American Association for Cancer Research
Browse
21598290cd201066-sup-247687_2_supp_6955969_qp6d82.pdf (1.78 MB)

Figure S3 from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Download (1.78 MB)
journal contribution
posted on 2023-04-03, 23:25 authored by Amir Arabzade, Yanhua Zhao, Srinidhi Varadharajan, Hsiao-Chi Chen, Selin Jessa, Bryan Rivas, Austin J. Stuckert, Minerva Solis, Alisha Kardian, Dana Tlais, Brian J. Golbourn, Ann-Catherine J. Stanton, Yuen San Chan, Calla Olson, Kristen L. Karlin, Kathleen Kong, Robert Kupp, Baoli Hu, Sarah G. Injac, Madeline Ngo, Peter R. Wang, Luz A. De León, Felix Sahm, Daisuke Kawauchi, Stefan M. Pfister, Charles Y. Lin, H. Courtney Hodges, Irtisha Singh, Thomas F. Westbrook, Murali M. Chintagumpala, Susan M. Blaney, Donald W. Parsons, Kristian W. Pajtler, Sameer Agnihotri, Richard J. Gilbertson, Joanna Yi, Nada Jabado, Claudia L. Kleinman, Kelsey C. Bertrand, Benjamin Deneen, Stephen C. Mack

Figure S3 demonstrating transcriptional alterations as a result of ZRfus loss of function

Funding

Cancer Prevention Research Institute of Texas

NIH-National Institute of Neurological Disease and Stroke

K12 award

Canadian Institutes of Health Research

NSERC

National Cancer Institute-Cancer Therapeutic Discovery

CPRIT

NCI

NIGMS

History

ARTICLE ABSTRACT

More than 60% of supratentorial 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, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZRfus-driven ependymoma. In addition to direct canonical NFκB 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 coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by PLAGL TF proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks. Ependymomas are aggressive brain tumors. Although drivers of supratentorial ependymoma (ZFTA- and YAP1-associated gene fusions) have been discovered, their functions remain unclear. Our study investigates the biology of ZFTA–RELA-driven ependymoma, specifically mechanisms of transcriptional deregulation and direct downstream gene networks that may be leveraged for potential therapeutic testing.This article is highlighted in the In This Issue feature, p. 2113

Usage metrics

    Cancer Discovery

    Categories

    Keywords

    Gene RegulationOncogenic transcription factorsPediatric Cancers

    Licence

    CC BY

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC