# Understanding Epigenetic Regulation of Copy Number Heterogeneity

> **NIH NIH R35** · UNIVERSITY OF COLORADO DENVER · 2024 · $421,200

## Abstract

PROJECT SUMMARY/ABSTRACT
The goal of my laboratory is to understand the role of extrachromosomal DNAs (ecDNA) in development and
stress response and how these processes are dysregulated during disease pathogenesis. EcDNA are linear or
circular fragments of DNA separate from the cells normal complement of chromosomes and have been identified
in multiple species and healthy tissues. ecDNA are elevated in cancer where they frequently harbor oncogenes
and can contribute to drug resistance and therefore may be important potential therapeutic targets. However,
we currently lack a fundamental understanding of the biogenesis, regulation, maintenance and selection of
ecDNA. My laboratory seeks to answer these fundamental questions surrounding ecDNA to facilitate
understanding the role of ecDNA in normal biological processes and their dysregulation in disease.
We have uncovered that multiple environmental stress responses cause cells to use targeted DNA rereplication
events to produce ecDNA. This MIRA proposal aims to understand which stress responses utilize ecDNA
production, identify the epigenetic regulators of these loci and develop methods to assess the importance of the
extra gene copies independent from the chromosomal locus. This work will provide fundamental insights into a
relatively unexplored pathway in environmental stress response that is quite commonly dysregulated in cancer.
The work in this MIRA represents roughly 50% of the work in the laboratory. Our other research projects
synergize with this work as they investigate the role of ecDNA in two disease contexts, breast cancer and Down
syndrome (DS). The work in breast cancer leverages newly discovered ecDNAs produced during epithelial to
mesenchymal transition as a potential novel therapeutic target to help reduce metastatic breast cancer. Our work
in DS investigates how cells with trisomy of chromosome 21 (T21; the genetic root of DS) fail to produce ecDNA
from stresses associated with comorbidities for individuals with DS.
In the next 5 years, the combined work from these projects will synergize to provide greater understanding on
the generation of ecDNA and their importance both in normal stress response and dysregulation in disease. We
will uncover novel methods to prevent ecDNA formation allowing us to assess the importance of the extra gene
copies independent of the endogenous chromosomal locus. We will establish a better fundamental
understanding of how epigenetics establish permissive chromatin environments for ecDNA production and have
identified specific enzymes that could be leveraged in the future as potential therapeutic targets. We will identify
signaling and regulatory pathways that control ecDNA connecting stress sensing to ecDNA production.

## Key facts

- **NIH application ID:** 10842722
- **Project number:** 2R35GM128720-06
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Joshua Cranston Black
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $421,200
- **Award type:** 2
- **Project period:** 2018-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842722

## Citation

> US National Institutes of Health, RePORTER application 10842722, Understanding Epigenetic Regulation of Copy Number Heterogeneity (2R35GM128720-06). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10842722. Licensed CC0.

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