Loss of HDAC3 contributes to meiotic defects in aged oocytes
Loss of HDAC3 contributes to meiotic defects in aged oocytes
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HDAC3 缺失导致衰老卵母细胞减数分裂缺陷
DOI：
10.1111/acel.13036
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发表时间：
2019-09-09
期刊：
影响因子：
7.8
通讯作者：
Gu, Ling
中科院分区：
文献类型：
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作者：
He, Yongfu;Li, Xiaoyan;Gu, Ling
母体年龄相关的卵母细胞质量下降与减数分裂缺陷有关，但其潜在机制仍有待探讨。组蛋白脱乙酰基酶3（HDAC 3）已显示通过脱乙酰化不同底物来控制多种细胞事件。我们以前发现HDAC 3可以促进小鼠卵母细胞减数分裂器的组装。在本研究中，我们确定了一个显着减少HDAC 3蛋白在卵母细胞从老年小鼠。更重要的是，HDAC 3在老卵母细胞中的过表达不仅部分防止了纺锤体/染色体的解体，而且还显著降低了非整倍体的发生率。同时，我们注意到老年小鼠卵母细胞中α-微管蛋白的乙酰化水平升高。通过定点突变，我们发现乙酰化模拟突变体微管蛋白-K40 Q破坏了小鼠卵母细胞中的着丝粒-微管连接，导致减数分裂器组装失败。重要的是，微管蛋白-K40 R（非乙酰化模拟突变体）的强制表达能够减轻老年小鼠卵母细胞的缺陷表型。综上所述，本研究揭示了HDAC 3的缺失是介导高龄产妇对卵母细胞质量影响的一种潜在机制。
Maternal age-related decline in oocyte quality is associated with meiotic defects, but the underlying mechanisms remain to be explored. Histone deacetylase 3 (HDAC3) has been shown to govern multiple cellular events via deacetylating diverse substrates. We previously found that HDAC3 could promote meiotic apparatus assembly in mouse oocytes. In the present study, we identified a substantial reduction in HDAC3 protein in oocytes from old mice. Importantly, overexpression of HDAC3 in old oocytes not only partially prevents spindle/chromosome disorganization, but also significantly lowers the incidence of aneuploidy. Meanwhile, we noticed the elevated acetylation level of alpha-tubulin in oocytes derived from old mice. By employing site-directed mutagenesis, we showed that acetylation-mimetic mutant tubulin-K40Q disrupts the kinetochore-microtubule attachments and results in the assembly failure of meiotic apparatus in mouse oocytes. Importantly, forced expression of tubulin-K40R (nonacetylatable-mimetic mutant) was capable of alleviating the defective phenotypes of oocytes from aged mice. To sum up, this study uncovers that loss of HDAC3 represents one potential mechanism mediating the effects of advanced maternal age on oocyte quality.