DNA comethylation analysis reveals a functional association between BRCA1 and sperm DNA fragmentation
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Updated: Oct 1, 2025
Methyl-binding DNA capture Sequencing for Patient Tissues
Published on: October 31, 2016
Weijian Zhu1, Lei Jiang1, Yan Li2
1Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
Insights
Sperm DNA fragmentation (SDF) is linked to specific DNA comethylation patterns. The gene BRCA1 was identified as a key player in sperm DNA damage, showing hypermethylation and reduced expression in cases of high fragmentation.
Area of Science:
- Epigenetics and Reproductive Medicine
- Sperm Biology and DNA Integrity
- Genetics of Male Infertility
Background:
- Sperm DNA fragmentation (SDF) is a significant factor in male infertility.
- Understanding the epigenetic mechanisms underlying SDF is crucial for reproductive health.
- Genome-wide DNA methylation patterns in sperm are increasingly recognized for their role in fertility.
Purpose of the Study:
- To identify DNA comethylation patterns associated with sperm DNA fragmentation (SDF).
- To explore the potential role of hub genes, particularly BRCA1, in the development of SDF.
- To investigate the functional impact of BRCA1 alterations on sperm DNA damage and repair.
Main Methods:
- Comethylation network analysis of genome-wide methylation profiles in sperm DNA from infertile men.
- Targeted bisulfite amplicon sequencing and droplet digital polymerase chain reaction to assess DNA methylation and fragmentation index (DFI).
- In vitro studies using mouse GC2 spermatocyte cells to model the role of Brca1 in DNA damage and oxidative stress.
Main Results:
- A distinct cluster of comethylated DNA patterns was identified in relation to SDF.
- BRCA1 was identified as a hub gene, with promoter hypermethylation and reduced mRNA expression correlating with higher DFI.
- In vitro, Brca1 knockdown impaired cell proliferation, increased oxidative stress sensitivity, and promoted DNA double-strand breaks.
Conclusions:
- Specific DNA comethylation patterns are associated with sperm DNA fragmentation.
- BRCA1 emerges as a critical gene involved in sperm DNA damage, potentially through epigenetic regulation.
- These findings highlight the role of epigenetics in male infertility and suggest BRCA1 as a potential therapeutic target.
Objectives:
To identify the DNA comethylation patterns associated with sperm DNA fragmentation (SDF) and to explore the potential associations of hub genes with SDF.
Design:
Prospective study.
Setting:
University-affiliated reproductive medicine center.
Patient(S):
A total of 300 male patients consulting for couple infertility were recruited from the First Affiliated Hospital of Wenzhou Medical University.
Intervention(S):
None.
Main Outcome Measure(S):
Comethylation network analysis based on the genome-wide methylation profile of spermatozoal DNA from 20 men was performed to identify hub modules and genes involved in SDF. Human spermatozoa were used for targeted bisulfite amplicon sequencing (267 men) or droplet digital polymerase chain reaction (45 men). The potential role of Brca1 in DNA damage was explored in mouse GC2 spermatocyte cells. Oxidative damage to spermatocytes was modeled by incubating GC2 cells with H2O2 (25 mM) for 90 minutes.
Result(S):
BRCA1 was identified as a hub gene in SDF. Promoter hypermethylation of BRCA1 was observed in those samples with a high DNA fragmentation index (DFI) compared to those with a low DFI. Concomitantly, BRCA1 mRNA expression was lower in samples with a high DFI than with a low DFI. In the GC2 cell model, Brca1 knockdown reduced cell proliferation and increased sensitivity to oxidative stress. Moreover, it increased double-strand breaks and decreased the protein levels of the DNA repair genes MRE11 and RAD51.
Conclusion(S):
A prominent cluster of comethylated patterns associated with SDF was identified. BRCA1 may be the hub gene involved in sperm DNA damage.
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