Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Biol Reprod. 2009 Dec;81(6):1164-71. doi: 10.1095/biolreprod.109.078386. Epub 2009 Jul 29.
The reproductive potential of mammals decreases with aging, until reaching infertility. One reason for aging-related infertility is the decrease of the reproductive capability of old oocytes. It was found previously that gene expression, histone acetylation, and protein function are altered by aging in metaphase II (MII) stage oocytes. MII oocytes develop from germinal vesicle (GV)-stage oocytes. Here, we hypothesized that the defects of old MII oocytes arise at the GV stage. To prove this hypothesis, we examined the acetylations of histone H4 at lysines 5 (H4K5), 8 (H4K8), 12 (H4K12), and 16 (H4K16) in old GV and MII oocytes. We found that acetylation of H4K12 and H4K16 decreased in old GV oocytes. Acetylation of H4K12 later increased in old MII oocytes. We also examined expression of Cdc2a, a gene related to H4K12 acetylation. Cdc2a expression increased in old nonsurrounded nucleolus (NSN) oocytes but decreased in old MII oocytes. On the other hand, the protein and kinase activities of CDC2A decreased in both GV and MII old oocytes. Finally, we showed that correction of the histone deacetylation of old oocytes at the GV stage restores younglike levels of H4K12 acetylation and CDC2A protein at the MII stage. These data support our hypothesis that abnormalities of histone acetylation at the GV stage are the cause of alterations at the MII stage. Our study provides evidence for strategies targeting the GV stage of oocytes to overcome aging-induced infertility.
哺乳动物的生殖能力随着衰老而下降，直到达到不育的程度。与衰老相关的不孕的一个原因是老化卵母细胞生殖能力的下降。先前已经发现，在中期 II (MII) 期卵母细胞中，基因表达、组蛋白乙酰化和蛋白质功能会因衰老而改变。MII 卵母细胞由生发泡期 (GV) 卵母细胞发育而来。在这里，我们假设老年 MII 卵母细胞的缺陷出现在 GV 期。为了证明这一假设，我们检查了老年 GV 和 MII 卵母细胞中组蛋白 H4 在赖氨酸 5 (H4K5)、8 (H4K8)、12 (H4K12) 和 16 (H4K16) 处的乙酰化。我们发现，老年 GV 卵母细胞中 H4K12 和 H4K16 的乙酰化减少。H4K12 的乙酰化在老年 MII 卵母细胞中后来增加。我们还检查了与 H4K12 乙酰化相关的基因 Cdc2a 的表达。Cdc2a 在老年无核仁包围 (NSN) 卵母细胞中的表达增加，但在老年 MII 卵母细胞中的表达减少。另一方面，CDC2A 的蛋白和激酶活性在 GV 和 MII 老年卵母细胞中均降低。最后，我们表明，在 GV 期纠正老年卵母细胞的组蛋白去乙酰化可恢复 MII 期年轻的 H4K12 乙酰化和 CDC2A 蛋白水平。这些数据支持我们的假设，即在 GV 期组蛋白乙酰化的异常是 MII 期改变的原因。我们的研究为靶向卵母细胞 GV 期的策略提供了证据，以克服衰老引起的不孕。
