# Epigenetics Landscape in the  Testes of Fertile and Infertile  Men

> **NIH NIH P50** · MAGEE-WOMEN'S RES INST AND FOUNDATION · 2021 · $114,697

## Abstract

Abstract: Pilot Project
In humans, 10-20% of infertile men are azoospermic, meaning that they lack spermatozoa. Of the two types,
non-obstructive (no blockage) azoospermia, in many cases, is idiopathic. Production of mature sperm involves
complex developmental processes, ultimately generating specialized cells for conception. Amongst these
processes includes epigenetic programming. While prenatal prospermatogonial genome-scale DNA
methylation programming has been well studied, the epigenetic landscape of postnatal testicular cells has not.
Current evidence suggests that aberrant epigenetic modifications may be one mechanism that leads to
idiopathic, non-obstructive azoospermia. However, this may relate to cell composition rather than etiologies of
spermatogenic failure. To distinguish between these possibilities, studies are required to determine whether
the epigenetic landscape of specific spermatogonial and Sertoli cells is altered in non-obstructive azoospermia.
In Aim 1, we hypothesize that aberrant epigenetic landscapes in postnatal spermatogonia play a role in
azoospermia due to etiology rather than whole testes cell composition. To test this hypothesis, we will use two
genetic mouse models with azoospermia to delineate whether DNA methylation and chromatin accessibility are
compromised. The first model will eliminate all de novo methyltransferase activity using conditional
Dnmt3a/Dnmt3b double mutants targeting the germ cell compartment, while the second model will employ the
androgen receptor knockout (SCARKOtm2.1) targeting the Sertoli compartment. In Aim 2, we hypothesis that
men with non-obstructive azoospermia will harbor aberrant DNA methylation and chromatin accessibility within
either the germ cell or Sertoli compartments. To test these hypothesis, we will produce DNA methylation,
chromatin accessibility and expression reference sequences from normal undifferentiated and differentiating
spermatogonia as well as Sertoli cells, following which we will compare the profile of these cells to those from
mutant mice, or men with maturation arrest or Sertoli cell only syndrome. For both aims, cells will be isolated
using the same enrichment strategy, and DNA methylation, chromatin accessibility and expression landscapes
for undifferentiated spermatogonia, differentiating spermatogonia and Sertoli cells will be generated using
NMT-seq (nucleosome, methylation and transcription sequencing), allowing comparative analysis between
mouse and human. Overall, we will produce foundational data about the epigenetic landscape in germ cells
and somatic cells of the testes and determine whether this landscape is altered in infertile mice and men.

## Key facts

- **NIH application ID:** 10137295
- **Project number:** 5P50HD096723-03
- **Recipient organization:** MAGEE-WOMEN'S RES INST AND FOUNDATION
- **Principal Investigator:** Mellissa Rae Wigle Mann
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $114,697
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137295

## Citation

> US National Institutes of Health, RePORTER application 10137295, Epigenetics Landscape in the  Testes of Fertile and Infertile  Men (5P50HD096723-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10137295. Licensed CC0.

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