# Interrogating the roles of canonical versus variant histone H3 in genome function during aging

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $40,496

## Abstract

PROJECT SUMMARY
Histone proteins package and organize DNA into chromatin, which regulates every DNA-dependent process.
Alterations to chromatin structure is a hallmark of aging and is characterized by global changes in gene
expression, histone abundance, histone PTM landscape, and chromatin accessibility. I propose that tight control
over histone abundance and histone type, which we term histone homeostasis, is essential for normal cellular
aging. Cells contain two histone types: canonical histones that are expressed during S phase of the cell cycle,
and variant histones that are expressed throughout the cell cycle and in non-dividing cells. Variant histones are
of particular interest to aging because they are the only source of new histones in non-dividing cells and
accumulate with age. Additionally, variant histone misregulation results in chromatin defects and reduced
lifespan. Knowing how canonical and variant histones regulate genome function is integral to understanding
normal and pathological chromatin-based aging processes. Canonical histone H3.2 and variant histone H3.3 are
some of the most highly conserved proteins across eukaryotes. The high conservation of amino acid differences
between canonical H3.2 and variant H3.3 suggests that they may perform unique functions in the genome, yet
it is not understood if variant H3.3 function is mediated by its cell-cycle independent expression or unique protein
sequence. In Drosophila, I have discovered that variant H3.3 is essential for development when canonical
histone gene copy number is reduced, suggesting a previously unknown requirement for coordination between
canonical H3.2 and variant H3.3 expression. However, the mechanisms underlying this coordination are
unknown. The proposed project tests the hypotheses that variant H3.3 is required for normal chromatin-based
aging processes and that cells possess a homeostatic mechanism to maintain the correct relative expression of
canonical H3.2 and variant H3.3 throughout development. The aims of this project are to (1) determine the
contributions of H3.3 expression versus protein sequence to chromatin-based aging processes and, (2) elucidate
the mechanisms that achieve proper H3 abundance through the coordination of canonical and variant histone
expression. This work will expand the fundamental understanding of how canonical and variant histones
cooperate to regulate genome function during aging.

## Key facts

- **NIH application ID:** 10831402
- **Project number:** 5F31AG079632-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Jeanne-Marie McPherson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $40,496
- **Award type:** 5
- **Project period:** 2023-05-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831402

## Citation

> US National Institutes of Health, RePORTER application 10831402, Interrogating the roles of canonical versus variant histone H3 in genome function during aging (5F31AG079632-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10831402. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*