# Contribution of DNA replication to epigenetic inheritance in a model multi-cellular organism

> **NIH NIH K99** · JOHNS HOPKINS UNIVERSITY · 2022 · $100,000

## Abstract

Asymmetric cell division (ACD) contributes to cellular diversity during development and adult tissue
homeostasis. ACD generates two genetically identical daughter cells with distinct cell fates influenced by the information
they inherit. Failure to properly regulate ACD leads to diseases such as tissue degeneration and cancer. An established
model of ACD are D. melanogaster male germline stem cells (GSCs). Our laboratory discovered that sister chromatids in
Drosophila male GSCs differentially incorporate histones based on when they were synthesized. The sisters are then
asymmetrically inherited. The sister with preexisting histones segregates to the self-renewing GSC whereas the sister with
newly synthesized histones segregates to the differentiating daughter cell. This extreme example of asymmetric sister
chromatid inheritance makes male GSCs a powerful system to study how distinct epigenetic information is established.
 DNA replication likely contributes to asymmetric histone deposition on sister chromatids because this is when the
majority of histones are incorporated into chromatin. Moreover, DNA replication is inherently asymmetric with DNA
being synthesized either continuously (leading strand) or discontinuously (lagging strand). Data from our laboratory
demonstrates that in GSCs, old histones recycle to the leading strand while the lagging strand incorporates new histones.
Similarly, biased histone incorporation is observed in mouse and yeast. Given this, DNA replication may have a
conserved, yet underappreciated role in establishing sister chromatid asymmetries. Using male Drosophila GSCs, this
proposal asks, “How does DNA replication contribute to histone asymmetries that influence cell fate decisions?”
 As leading and lagging strands switch at replication initiation and termination zones, it is unclear how local
asymmetries at the replication fork produce sister chromatids mostly enriched for either new or old histones. While this is
the long-term goal of this research, it is necessary to first define the epigenetic and DNA replication landscapes in GSCs.
Due to the small number of GSCs in wildtype tissue, genomic studies are historically challenging. However, a GSC-like
tumor system provides the unprecedented opportunity to use this technology. In the K99 stage, the GSC-like tumor system
will be used to develop a novel cell-specific Chromatin Immuno-Cleavage-sequencing assay to profile histone
modifications specifically in GSCs. Further, replication timing will be defined through Replication-sequencing. The
results of these experiments are integral to investigate genome-wide associations of histone populations in replicating
regions. Further, genetic experiments will test if histone chaperones contribute to the local histone asymmetries observed
in GSCs. These studies will be expanded upon during the R00 stage to investigate the contribution of DNA replication-
coupled histone assembly to somatic epigenetic inheritance during developme...

## Key facts

- **NIH application ID:** 10427733
- **Project number:** 1K99GM145973-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Jennifer Anne Urban
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $100,000
- **Award type:** 1
- **Project period:** 2022-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427733

## Citation

> US National Institutes of Health, RePORTER application 10427733, Contribution of DNA replication to epigenetic inheritance in a model multi-cellular organism (1K99GM145973-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10427733. Licensed CC0.

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