# Manipulation of three-dimensional chromatin structure to regulate oncogenes in breast and ovarian cancer.

> **NIH NIH K00** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $96,563

## Abstract

It has become increasingly apparent in recent years that the chromosomal contacts created by the three-dimensional
(3D) organization of the genome are critical in the regulation of gene expression. Disruption of this
structure has been strongly implicated in the vast alterations in gene expression that are observed in many
cancers, and there is increasing evidence that alterations in chromatin structure surrounding key oncogenes,
such as myc, may be of significant importance in both driving oncogenesis and in sustaining disease. Despite
this knowledge, it remains unclear whether alterations in chromatin structure are a cause or a consequence of
alterations in transcriptional activity. This is in large part due to a limited availability of tools to study single
chromatin contacts. Reported methods for forcibly looping distant genomic regions have frequently involved
either gross alterations of the linear DNA sequence or are technically challenging and demand significant prior
knowledge of loop-mediating factors. To address these issues, I have developed a novel technology for
chromatin loop re-organization using CRISPR-dCas9 (CLOuD9) that allows for a versatile, targeted, and
reversible manipulation of chromatin contacts. I have demonstrated the utility of CLOuD9 to modulate gene
expression in human cells, and plan to further utilize it to investigate how differential enhancer contacts can
regulate expression of myc in breast and ovarian cancer (BOC). I hypothesize that alteration of the chromatin
contacts surrounding the myc locus is sufficient to alter myc expression, and thereby impact the development
and progression of these cancers. In the future, I plan to investigate the mechanisms by which dysregulation of
chromatin structure contributes to acquired chemoresistance on a genome-wide scale. Collectively, findings
from this body of work will be critical to obtaining a more comprehensive understanding of how chromatin
dynamics specifically impact transcription apparatus to facilitate oncogenesis, and may further shed light on
useful ways to design novel therapies for more targeted cancer treatments.

## Key facts

- **NIH application ID:** 9932946
- **Project number:** 5K00CA222541-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Stefanie L Morgan
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $96,563
- **Award type:** 5
- **Project period:** 2018-07-06 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932946

## Citation

> US National Institutes of Health, RePORTER application 9932946, Manipulation of three-dimensional chromatin structure to regulate oncogenes in breast and ovarian cancer. (5K00CA222541-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9932946. Licensed CC0.

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