# Developmental control of chromatin states in cancer

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $414,512

## Abstract

SUMMARY
Ewing sarcoma, a cancer of the bone and soft tissue of children and young adults, remains a highly lethal cancer
despite the use of aggressive chemotherapy, radiation, and surgery. The tumor is dependent on the development
of a hybrid gene that brings together parts of two different genes, EWSR1 and FLI1, through chromosomal
translocation or chromoplexy. The resulting EWS-FLI1 fusion oncoprotein acts as a transcriptional and chromatin
regulator. Building from the work of our lab and others demonstrating that EWS-FLI1 gains neomorphic activity
to regulates chromatin state at microsatellite coopted to become enhancers in tumor cells. However, we have
shown that the activity and genomic targeting of EWS-FLI1 is influenced by the underlying epigenomic state of
the cell. We demonstrated that primary and in vitro differentiated mesenchymal stem cells offer a chromatin state
similar to that of Ewing sarcoma. We hypothesize that during stem cell differentiation a unique permissive
chromatin state develops that enables EWS-FLI1. Further, we hypothesize that this permissive state is made
up of chromatin regulators, characteristically modified histones and specific RNAs. In this project we will
employ cancer cell (Aim 1) and stem cell developmental approaches (Aim 2) to identify the protein and RNA
interactors and the posttranslational modifications of histones that create a favorable environment. We predict
that critical features will be shared between both model systems. We will test the impact of these factors by
evaluating the activity of EWS-FLI1 on chromatin states and transcription when these factors are modulated.
The generation of Ewing sarcoma patient derived stem cells will enable us to evaluate the impact of EWS-FLI1
across the process of cellular differentiation. Integrated single cell analytics of chromatin accessibility and the
transcriptome will enable direct evaluation of the impact of EWS-FLI1 on chromatin and, reciprocally, chromatin
on EWS-FLI1. We will specifically study the biochemical interaction and functional relationship between
EWS-FLI1 and the transcriptional regulator PAX7, one of the interactors identified during pilot
experimentation.

## Key facts

- **NIH application ID:** 10757436
- **Project number:** 5R01CA276663-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Ian J Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $414,512
- **Award type:** 5
- **Project period:** 2023-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757436

## Citation

> US National Institutes of Health, RePORTER application 10757436, Developmental control of chromatin states in cancer (5R01CA276663-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10757436. Licensed CC0.

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