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Aging alters histone H3 lysine 4 methylation in mouse germinal vesicle stage oocytes
Gen-Bao Shao1, Jie Wang2, Liu-Ping Zhang1
1Department of Biology, Jiangsu University, School of Medical Science and Laboratory Medicine, Zhenjiang 212013, P. R. China.
Abstract:
Decreasing oocyte competence with maternal aging is a major factor in mammalian infertility. One of the factors contributing to this infertility is changes to chromatin modifications, such as histone acetylation in old MII stage oocytes. Recent studies indicate that changes in histone acetylation at MII arise at the germinal vesicle (GV) stage. We hypothesised that histone methylation could also change in old GV oocytes. To test this hypothesis, we examined mono-, di- and trimethylation of histone H3 lysine 4 (H3K4 me1, me2 and me3, respectively) in young and older oocytes from 6-8- and 42-44-week-old mice, respectively. We found that H3K4 me2 and me3 decreased in older compared with young GV oocytes (100% vs. 81% and 100% vs. 87%, respectively; P<0.05). H3K4 me2 later increased in older MII oocytes (21% vs. 56%; P<0.05). We also examined the expression of genes encoding the H3K4 demethylases lysine (K)-specific demethylase 1A (Kdm1a) and retinol binding protein 2 (Rbp2). Expression of Kdm1a increased at both the mRNA and protein levels in older GV oocytes, but decreased in older MII oocytes (P<0.05), and was negatively correlated with H3K4 me2 levels. Conversely, expression of Rbp2 mRNA and protein decreased in older GV oocytes (P<0.05), and this was not correlated with H3K4 me3 levels. Finally, we showed that inhibition of Kdm1a of older oocytes at the GV stage restored levels of H3K4 me2 at the MII stage to those seen in 'young' oocytes (41% vs. 38%; P>0.05). These results suggest that changes in expression of H3K4 me2 and Kdm1a in older GV oocytes may represent a molecular mechanism underlying human infertility caused by aging.
Insights
Maternal aging reduces oocyte quality, partly due to altered histone methylation. This study found changes in histone H3 lysine 4 (H3K4) methylation and demethylase Kdm1a expression in aging mouse oocytes, suggesting a mechanism for infertility.
Area of Science:
- Reproductive Biology
- Epigenetics
- Mammalian Oogenesis
Background:
- Maternal aging is a primary cause of mammalian infertility.
- Chromatin modifications, including histone acetylation, are implicated in age-related oocyte dysfunction.
- Histone methylation changes in aging oocytes remain largely unexplored.
Purpose of the Study:
- To investigate alterations in histone H3 lysine 4 (H3K4) methylation patterns in oocytes from aged mice.
- To examine the expression of H3K4 demethylases, Kdm1a and Rbp2, in young versus aged oocytes.
- To determine if Kdm1a activity contributes to age-related changes in H3K4 methylation.
Main Methods:
- Immunofluorescence staining to assess H3K4 (mono-, di-, trimethylation) levels in germinal vesicle (GV) and MII stage oocytes from young and aged mice.
- Quantitative real-time PCR and Western blotting to measure mRNA and protein expression of Kdm1a and Rbp2.
- Pharmacological inhibition of Kdm1a in aged GV oocytes to assess its impact on H3K4 me2 levels at the MII stage.
Main Results:
- Aged GV oocytes showed decreased levels of H3K4 di- and trimethylation compared to young oocytes.
- H3K4 dimethylation levels increased in aged MII oocytes.
- Kdm1a expression (mRNA and protein) was elevated in aged GV oocytes but decreased in aged MII oocytes, correlating negatively with H3K4 me2.
- Rbp2 expression decreased in aged GV oocytes.
- Inhibition of Kdm1a in aged GV oocytes restored H3K4 me2 levels at the MII stage.
Conclusions:
- Age-associated changes in H3K4 methylation, specifically a decrease in H3K4 di- and trimethylation in GV oocytes, occur during mammalian oogenesis.
- Altered expression of H3K4 demethylase Kdm1a in aging oocytes is linked to these methylation changes.
- These epigenetic modifications may represent a molecular pathway contributing to infertility in older females.
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