# Investigating chromatin mechanisms using viral systems

> **NIH NIH R35** · FRED HUTCHINSON CANCER CENTER · 2024 · $484,000

## Abstract

PROJECT SUMMARY
The eukaryotic genome is compacted in a basic repeating structure called chromatin, the anomalous regulation
of which is characteristic of many diseases. In recent years, the technologies to study chromatin have leapt
forward, allowing us to investigate chromosome interactions in three dimensions. However, these methods rely
on measurements taken at a baseline state, thus, a barrier remains to understanding the biological functions of
chromatin in a dynamic system. It has become increasingly evident that viruses manipulate the nuclear
environment to generate viral progeny, necessarily hijacking host chromatin resources for viral benefit.
Therefore, virus infection provides an ideal dynamic system in which to investigate chromatin function. Moreover,
interrogating virus-host interactions has led to advances in virus biology and the discovery of some of the most
profound areas of molecular biology ranging from p53 to splicing. With the recent advances in chromatin
methodologies, we are now in an ideal position to take the next step in understanding chromosome biology in
the three-dimensional context of dynamic biological systems. In this proposal, we aim to employ cutting-edge
chromatin technology combined with virus infection to reveal fundamental chromatin functions. We
focus on nuclear replicating viruses, adenoviruses and multiple herpesviruses, as test cases for the virus to
pinpoint vulnerabilities in chromatin function exploited by pathogens. We have successfully identified three
scenarios in which cellular chromatin is distinctly reorganized for viral benefit: 1) adenovirus protein VII causes
global chromatin reorganization through linker histone displacement to disrupt the cell cycle and impact
transcription; 2) herpes simplex virus infection causes marginalization of host chromatin by generating new
regions of heterochromatin that promote egress of viral progeny; and 3) human cytomegalovirus polarizes
cellular chromatin to generate a functional viral assembly center. We will systematically investigate the
mechanisms by which these dramatic nuclear rearrangements occur in three dimensions using a combination of
high-resolution immunofluorescence microscopy, electron microscopy, and chromosome capture techniques. In
the previous funding period, our approaches defined multiple previously unknown vulnerabilities of chromatin,
positioning us to take the next step into understanding the mechanisms of chromatin organization in the nucleus
in 3D. Completion of these studies will identify new chromatin targets and assist development of innovative
therapies for cancer, inflammation, and viral diseases.

## Key facts

- **NIH application ID:** 10842160
- **Project number:** 2R35GM133441-07
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Daphne Christina Avgousti
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $484,000
- **Award type:** 2
- **Project period:** 2019-09-01 → 2025-02-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842160

## Citation

> US National Institutes of Health, RePORTER application 10842160, Investigating chromatin mechanisms using viral systems (2R35GM133441-07). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10842160. Licensed CC0.

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