# Investigating the role of bromodomain-containing proteins in the production of viable spermatozoa and male fertility

> **NIH NIH P50** · CORNELL UNIVERSITY · 2024 · $386,957

## Abstract

Spermatogenesis is a highly unique differentiation process that involves complex mechanisms of gene
regulation, particularly at the level of the transcriptional machinery. The complexity of this process is
underscored by the fact that 30% of male infertility is attributable to sperm morphology defects and/or poor
semen quality. Bromodomain-containing (BD) proteins are critical regulators of transcription, which act by
binding acetylated histone residues at their target loci and recruiting the appropriate transcriptional regulators.
Mutations in the genes encoding three BD proteins (BRDT, BRD4 and BRWD1), or that of their interacting
proteins, result in morphologically abnormal sperm in mice, and have been associated with poor semen quality
and infertility in men. We hypothesize that BRDT, BRD4, and BRWD1 play interconnected roles during
meiotic prophase I and spermiogenesis, two key stages of spermatogenesis during which stringent
transcriptional regulation is exerted, to ensure appropriate transcriptional control and chromatin
compaction leading to the production of morphologically normal sperm. We propose the following model:
(1) during meiotic prophase I, BRDT ensures appropriate temporo-spatial control of transcriptional repression
to allow for the events of recombination and synapsis; (2) then, upon entry into spermiogenesis, BRDT aids in
chromatin compaction during histone-to-protamine exchange, by shutting down transcription across the
genome; (3) at the same time, BRD4 and BRWD1 are required to overcome the transcriptional silencing
imposed by BRDT specifically at genes essential for spermatid development. Studies herein will test this
integrated model of BD action in mice and men. In Aim 1, we will elucidate the role of BRDT in mediating
progressive transcriptional shut down during meiotic prophase I using a mouse mutant lacking Brdt. We will
examine meiotic progression in wildtype and mutant spermatocytes, and will define the genome-wide
distribution of BD proteins and components of the transcriptional machinery. We will ask whether BRDT
function is dependent on synapsis or recombination. In Aim 2, we will explore the role of BRWD1 and BRD4 in
overcoming BRDT-mediated repression and ensuring expression of critical spermatid differentiation genes. We
will investigate how BD proteins co-operate to ensure the correct chromatin environment is in place to allow for
the progressive nuclear compaction that arises due to the histone-to-protamine exchange. In Aim 3, we will
map the genome-wide distribution of BRDT and BRWD1, histone acetylation, and transcription in human testis,
with matched analysis of sperm morphology. By combining these data with analysis of sperm chromatin
compaction in wildtype and BD knockout mice, we will develop machine learning tools that permit stratification
of sperm from infertile men based on BD protein function and chromatin compaction. These studies are the
first to elucidate the coordinated roles of BD proteins ...

## Key facts

- **NIH application ID:** 10828825
- **Project number:** 5P50HD104454-04
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Paula Elaine Cohen
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $386,957
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828825

## Citation

> US National Institutes of Health, RePORTER application 10828825, Investigating the role of bromodomain-containing proteins in the production of viable spermatozoa and male fertility (5P50HD104454-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10828825. Licensed CC0.

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