# Epigenetic mechanisms in oncogenic genome organization

> **NIH NIH FI2** · NATIONAL CANCER INSTITUTE · 2022 · —

## Abstract

Project Summary/Abstract
Activation and maintenance of cancer related pathways is associated with re-organization of the genome and
chromatin landscape. Chromatin structure is important for genome function and is regulated by epigenetic
modulators and architectural proteins. Epigenetic modulators have been shown to promote pro-oncogenic gene
expression profiles making these factors the focus of studies to identify biomarkers and druggable targets in
cancer cells. However, the mechanism and factors that regulate genome organization during oncogenic
processes are largely unknown. The genome is organized into loops and topologically associated domains
(TADs), which are formed by the ATP-dependent cohesin complex and maintained by binding of the architectural
protein CTCF at domain boundaries. We hypothesize that epigenetic factors contribute to re-organization
of key genomic loci during oncogenesis including the MYC locus. The goal of this proposal is to
characterize cancer specific genome organization using the MYC locus as a model and gain insight into
epigenetic mechanisms that regulate architectural proteins. In Aim 1 we will use single-molecule imaging to map
the 3 Mb MYC locus by DNA fluorescence in situ hybridization (FISH) in colorectal cancer cells. We will also
characterize the functional role of nuclear 3D positioning for the MYC locus and association with nuclear
structures. In Aim 2 we will identify epigenetic modulators that regulate genome organization at the MYC locus
in colorectal cancer cells by performing a high-throughput CRISPR based imaging screen using DNA FISH. We
will also elucidate the mechanism by which these factors organize the genome and regulate CTCF and cohesins
by mass spectrometry, high-resolution mapping, and ChIP-seq. Finally, in Aim 3 we will map organizational
changes at the MYC locus in response to the induction of epithelial-to-mesenchymal transition (EMT), a process
associated with invasiveness in cancer. Additionally, in Aim 3 we will determine how architectural proteins
regulate EMT marker genes and the phenotypes associated with this cellular transition. The studies outlined in
this proposal will determine how changes to oncogenic genome organization occur at the single cell level and
identify novel epigenetic factors previously uncharacterized for their roles in regulating genome organization in
colorectal cancer cells and during EMT.

## Key facts

- **NIH application ID:** 10498387
- **Project number:** 1FI2GM146623-01
- **Recipient organization:** NATIONAL CANCER INSTITUTE
- **Principal Investigator:** Theodore Busby
- **Activity code:** FI2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498387

## Citation

> US National Institutes of Health, RePORTER application 10498387, Epigenetic mechanisms in oncogenic genome organization (1FI2GM146623-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10498387. Licensed CC0.

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