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Updated: Dec 28, 2025
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Published on: October 11, 2022
UHRF1-repressed 5'-hydroxymethylcytosine is essential for the male meiotic prophase I
Hongjie Pan1, Ning Jiang2, Shenfei Sun1
1National Health Commission (NHC) Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, 200032, Shanghai, P.R. China.
Abstract:
5'-hydroxymethylcytosine (5hmC), an important 5'-cytosine modification, is altered highly in order in male meiotic prophase. However, the regulatory mechanism of this dynamic change and the function of 5hmC in meiosis remain largely unknown. Using a knockout mouse model, we showed that UHRF1 regulated male meiosis. UHRF1 deficiency led to failure of meiosis and male infertility. Mechanistically, the deficiency of UHRF1 altered significantly the meiotic gene profile of spermatocytes. Uhrf1 knockout induced an increase of the global 5hmC level. The enrichment of hyper-5hmC at transcriptional start sites (TSSs) was highly associated with gene downregulation. In addition, the elevated level of the TET1 enzyme might have contributed to the higher 5hmC level in the Uhrf1 knockout spermatocytes. Finally, we reported Uhrf1, a key gene in male meiosis, repressed hyper-5hmC by downregulating TET1. Furthermore, UHRF1 facilitated RNA polymerase II (RNA-pol2) loading to promote gene transcription. Thus our study demonstrated a potential regulatory mechanism of 5hmC dynamic change and its involvement in epigenetic regulation in male meiosis.
Insights
The study reveals UHRF1 is crucial for male meiosis and fertility. UHRF1 deficiency increases 5hmC, repressing genes essential for male reproductive cell development.
Area of Science:
- Epigenetics
- Reproductive Biology
- Molecular Biology
Background:
- 5'-hydroxymethylcytosine (5hmC) dynamics are critical in male meiosis but poorly understood.
- The regulatory mechanisms and functional roles of 5hmC in male reproductive cell development remain largely unknown.
Purpose of the Study:
- To investigate the role of UHRF1 in male meiosis.
- To elucidate the regulatory mechanism of 5hmC changes during male meiosis.
- To understand the function of 5hmC in male reproductive cell epigenetic regulation.
Main Methods:
- Utilized a UHRF1 knockout mouse model.
- Analyzed meiotic gene expression profiles in spermatocytes.
- Assessed global and targeted 5hmC levels.
- Investigated the interaction between UHRF1, TET1, and RNA polymerase II.
Main Results:
- UHRF1 deficiency caused meiotic failure and male infertility.
- UHRF1 knockout led to increased global 5hmC levels.
- Hyper-5hmC enrichment at transcriptional start sites correlated with gene downregulation.
- UHRF1 was found to repress hyper-5hmC by downregulating TET1 and facilitate RNA polymerase II loading.
Conclusions:
- UHRF1 is essential for regulating male meiosis and fertility.
- The study demonstrates a novel epigenetic regulatory mechanism involving UHRF1 and 5hmC in male meiosis.
- UHRF1 controls 5hmC levels and gene transcription, impacting male reproductive cell development.
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