# Understanding Epigenetic Regulation of Copy Number Heterogeneity

> **NIH NIH R35** · UNIVERSITY OF COLORADO DENVER · 2020 · $379,646

## Abstract

PROJECT SUMMARY/ABSTRACT
 Eukaryotic cells maintain tight control over DNA replication to guarantee that each
daughter cell receives one and only one copy of the genetic material. Initiation of DNA replication
more than once per cell cycle, or rereplication, results in increased gene amplification and
aneuploidy, which are critical parameters that contribute to tumorigenesis and tumor progression.
Genome-wide analysis of copy number variation in hematopoietic and solid cancers has identified
chromosomal regions with higher frequencies of gain or amplification, which often contain pro-
survival and/or oncogenes. Therefore, understanding how rereplication and amplification of
specific regions emerge and potentiate cancer development and drug resistance will impact our
understanding of hard to treat malignancies.
 The work in this proposal challenges the dogmatic interpretation of DNA replication as a
once-per-cell cycle event. My research program is designed to understand how prevalent
rereplication is, identify the molecular determinants that specify regions for rereplication, and
uncover methods to intervene to block unwanted rereplication. The work in this proposal will
rigorously test how epigenetics regulates DNA rereplication. We will apply our new technology,
RerepSeq, for the enrichment and unbiased identification of regions that undergo DNA
rereplication. Through developing the network of rereplicated sites we can understand what
pathways and features contribute to their origins. Our initial work will focus on two epigenetically
driven models of rereplication. We will identify the specific network of epigenetic regulatory
factors that drives rereplication at these loci and determine how we can prevent the rereplication
from happening.
 In five years, the work from this proposal will have established how two different epigenetic
pathways, H3K27me3 and DNA methylation, regulate rereplication. This work will have uncovered
fundamental properties of rereplicated regions including size, epigenetic state and functional
relevance to cell biology. These two initial models will establish the procedures, reagents and
tools to investigate other epigenetically regulated regions of rereplication identified through our
unbiased sequencing approach, which will be the basis of future work in the laboratory. Our goal
is to uncover the entire epigenetic addressing system that directs rereplication. By understanding
this network, we can exploit it to prevent rereplication of drug resistance or oncogenes to facilitate
better treatment.

## Key facts

- **NIH application ID:** 9980943
- **Project number:** 5R35GM128720-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Joshua Cranston Black
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $379,646
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980943

## Citation

> US National Institutes of Health, RePORTER application 9980943, Understanding Epigenetic Regulation of Copy Number Heterogeneity (5R35GM128720-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9980943. Licensed CC0.

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