# Epigenetic control of spermatogonial stem cell self-renewal

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $386,155

## Abstract

Project Summary
 Males produce sperm continuously through adult life, driven by the renewal of spermatogonial stem cells
(SSCs). The long-term objective of this application is to determine the role of a novel epigenetic program that
we have recently identified in regulating the renewal of adult SSCs. SSCs can both self-renew and produce
progenitor spermatogonia that will differentiate to initiate spermatogenesis. The balance between SSC self-
renewal and differentiation is key for life-long production of sperm in adult males. Both SSC transplantation and
in vitro SSC cultures have enabled functional studies of SSC and allowed for advancement of translational
applications in animal transgenesis. However, while much is known about spermatogenesis, the regulation of
SSC self-renewal remains poorly understood. Stem cell renewal requires both stem cell-intrinsic factors and
external niche factors, only a handful of which have been identified (PLZF, RB, NANOS2, GDNF, ETV5, etc.).
Notably, their functions in SSC self-renewal have been revealed through genetic studies. Despite these
advances, the molecular biological control of SSC remains poorly understood. We have identified an
epigenetic factor DOT1L, the sole H3K79 methyltransferase, as a novel master regulator of mouse SSC self-
renewal. Moreover, by chemically inhibiting DOT1L, we were able to identify specific target genes that likely
contribute to SSC renewal. We propose an innovative multi-pronged (genetic, chemical, genomic, and
proteomic) approach to comprehensively elucidate this novel epigenetic program in SSCs. As failure in SSC
self-renewal leads to a lack of sperm production and thus male infertility, completion of this project will lay a
firm foundation for molecular dissection of SSC stem cell renewal and open new avenues of research in SSC
biology and reproductive medicine.

## Key facts

- **NIH application ID:** 10854935
- **Project number:** 5R01HD109253-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Peijing Jeremy Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $386,155
- **Award type:** 5
- **Project period:** 2023-06-05 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10854935

## Citation

> US National Institutes of Health, RePORTER application 10854935, Epigenetic control of spermatogonial stem cell self-renewal (5R01HD109253-02). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10854935. Licensed CC0.

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