# Understanding the roles of histone H3 variants in promoting genomic and epigenomic stability during DNA replication and aging

> **NIH NIH R35** · YALE UNIVERSITY · 2021 · $418,557

## Abstract

Project Summary:
Maintaining genome and epigenome stability is required in both mitotic and post-mitotic
cells to prevent deleterious mutations that can cause diseases like cancer and
neurodegenerative disorders. In proliferative cells, DNA replication needs to be
coordinated with transcription and DNA repair to prevent the occurrence and inheritance
of mutations. In terminally differentiated, non-replicating cells like neurons, chromatin has
to be stable for long periods of time to maintain established transcriptional programs. With
this proposal, we seek to understand the contributions of histone H3 variants to genomic
and epigenomic stability during DNA replication and aging. Levels of replication-
dependent H3.1/H3.2 variants and replication-independent H3.3 variants change
drastically during DNA replication in proliferating cells and through time in post-mitotic
cells. We have shown previously that H3.1 and H3.3 variants can have different
biochemical functions on the epigenome in plants, which are mediated by a variable amino
acid residue (position 31) in the N-terminal tail of these two highly conserved proteins.
Through the study of the H3K27 methyltransferases ATXR5 and ATXR6 (ATXR5/6), we
have demonstrated that newly synthesized H3.1 variants are specifically methylated by
ATXR/6 during DNA replication, and that H3.1 variants unmethylated at K27
(H3.1K27me0), but not H3.3K27me0, induce genomic instability. We will investigate the
biochemical and cellular mechanisms by which H3.1 regulates genomic stability in plants
using genetic and biochemical screens for chromatin-interacting proteins that can
discriminate between H3.1 and H3.3. We will also use a histone replacement strategy to
analyze the roles of all histones in maintaining or disrupting genomic stability during DNA
replication. Finally, we will replicate these experiments to study the role of H3 variants in
maintaining heterochromatin in aging neurons using Drosophila as a model system. The
high levels of similarity between H3.1, H3.3 and chromatin-modifying proteins across all
eukaryotes suggest that the molecular mechanisms that will be uncovered through this
work will be conserved in humans and involved in diseases caused by genomic or
epigenomic instability.

## Key facts

- **NIH application ID:** 10219301
- **Project number:** 5R35GM128661-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** YANNICK JACOB
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $418,557
- **Award type:** 5
- **Project period:** 2018-08-07 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219301

## Citation

> US National Institutes of Health, RePORTER application 10219301, Understanding the roles of histone H3 variants in promoting genomic and epigenomic stability during DNA replication and aging (5R35GM128661-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10219301. Licensed CC0.

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