# Transcriptional Regulation in ZFTA-RELA Ependymoma

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $591,375

## Abstract

SUMMARY
Transcriptional networks in cancer are a collection of inputs from developmental and cell identity programs,
oncogenic proteins, metabolic circuits, and micro-environmental interactions. Together, these culminate to drive
disparate stages of tumor initiation, maintenance, and progression. Ependymoma (EPN) is an aggressive form
of pediatric brain cancer driven by a single genetic event, a gene fusion between ZFTA and RELA. ZFTA-RELA
(denoted ZRFUS) is a potent driver of transformation, and its expression is sufficient to induce EPN when
expressed in the developing mouse brain. Despite evidence that ZRFUS functions as an aberrant transcriptional
regulator, the downstream mechanisms it utilizes to drive tumorigenesis remain poorly defined. This knowledge
gap has hindered the identification of clinically tractable approaches for EPN, which have remained stagnant for
over 30 years. Therefore the overarching goal of this proposal is to dissect how ZRFUS impacts and
intersects with the diverse transcriptional programs that drive EPN tumorigenesis. To dissect how ZRFUS
drives EPN tumorigenesis, we established the first autochthonous mouse model of ZRFUS EPN using in utero
electroporation (IUE) of the developing mouse brain. Using this model, we demonstrated that transcription factor
(TFs) essential for developmental gliogenesis, such as SOX9, are required for the initiation of ZRFUS EPN
development. Barcode screening of these developmental TFs in our model identified ETV5 as a lead candidate
that is both necessary and sufficient for ZRFUS progression. Further examination of ETV5 function in EPN
revealed that it suppresses gene expression by promoting repressive chromatin states. Among the key target
genes repressed by ETV5 is Neuropeptide Y (NPY), a potent neurotransmitter, which we found functions to
suppress ZRFUS progression and remodel neuronal synapses in the peritumoral margins towards decreased
activity. Based on these compelling preliminary studies, we hypothesize that developmentally encoded TFs
govern tumor initiation and manipulate chromatin accessibility that regulate tumor-neuron interactions
in the brain microenvironment to drive EPN growth. This hypothesis will be tested in the following aims: 1)
Determine how SOX9 impacts ZRFUS EPN initiation through modifying chromatin accessibility, 2) Decipher the
role of ETV5 in ZRFUS EPN progression, and 3) Define the role of NPY in remodeling the ependymoma neuronal
microenvironment.

## Key facts

- **NIH application ID:** 10892870
- **Project number:** 5R01CA284455-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Benjamin Deneen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $591,375
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892870

## Citation

> US National Institutes of Health, RePORTER application 10892870, Transcriptional Regulation in ZFTA-RELA Ependymoma (5R01CA284455-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10892870. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*