# Biochemical studies of aberrant chromatin regulation in cancer

> **NIH NIH F99** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $47,536

## Abstract

Project Summary/Abstract
Eukaryotic cells require the tight regulation of global gene expression to maintain homeostasis
and respond to environmental stimuli. DNA spools around histone proteins form this vital
structure, chromatin, and provide a platform for the sophisticated tuning of gene expression
through physical and chemical regulation. Unsurprisingly, the disruption of these chromatin
regulatory mechanisms is particularly prevalent in cancers as a driver of disease. Completion of
the proposed projects will shed light on the mechanisms of healthy chromatin regulation and its
disruption in disease, providing the insight necessary to develop improved therapeutic
interventions in a variety of cancers.
 In the F99 phase of this proposal, I study disrupted chromatin signaling by Hepatitis B
Virus (HBV), a leading cause of hepatocellular carcinoma worldwide. HBV maintains chronic
infections within hepatocytes by establishing an independent minichromosome, termed covalently
closed circular DNA (cccDNA), that largely evades immune detection and conventional chromatin
regulatory mechanisms. Further contributing to this evasion is the viral protein HBx, which has
documented roles redirecting numerous chromatin effectors, including transcription factors,
degradation machinery, and epigenome modifiers. So far in my thesis work, I have developed a
platform to reconstitute cccDNA in vitro for biochemical and biophysical studies, determined that
histone occupancy in cccDNA is required for HBx expression, and shown that HBx binds directly
to nucleosomes. The remainder of my thesis work will be spent testing the biochemical effects of
other known interactors on cccDNA compaction and gene expression and illuminating the
cccDNA landscape in cells using locus-specific proteomic and epigenomic studies.
 The K00 phase shifts focus to ATP-dependent chromatin remodeling enzymes, a class of
proteins shown to be mutated or overexpressed in more than 20% of cancers. In particular, I
intend to study the CHD family of remodelers, which have been implicated as drivers of a variety
of cancer types. I will apply my expertise in chromatin biochemistry and expand my technical
repertoire to include cryo-electron microscopy as a means to study the structure and function of
CHD chromatin remodelers. In parallel, I will develop skills in gene editing techniques to knockout
wild-type enzyme and introduce clinically-relevant CHD mutants into cells for epigenomic
analyses of remodeler dysfunction in disease. Combining these new approaches with my
background in biochemistry, chemical biology, and biophysics will position me to address pressing
questions in chromatin and cancer biology throughout the rest of my career as I pursue an
independent, cancer-focused faculty position.

## Key facts

- **NIH application ID:** 10305344
- **Project number:** 1F99CA264420-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Nicholas Prescott
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $47,536
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10305344

## Citation

> US National Institutes of Health, RePORTER application 10305344, Biochemical studies of aberrant chromatin regulation in cancer (1F99CA264420-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10305344. Licensed CC0.

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