State Key Laboratory of Reproductive Medicine, Suzhou Municipal Hospital, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Aging (Albany NY). 2020 Jan 24;12(2):1610-1623. doi: 10.18632/aging.102703.
It has been widely reported that advanced maternal age impairs oocyte quality. To date, various molecules have been discovered to be involved in this process. However, prevention of fertility issues associated with maternal age is still a challenge. In the present study, we find that both supplement and administration of melatonin are capable of alleviating the meiotic phenotypes of aged oocytes, specifically the spindle/chromosome disorganization and aneuploidy generation. Furthermore, we identify SIRT2 as a critical effector mediating the effects of melatonin on meiotic structure in old oocytes. Candidate screening shows that SIRT2-controlled deacetylation of histone H4K16 is essential for maintaining the meiotic apparatus in oocytes. Importantly, non-acetylatable-mimetic mutant H4K16R partially rescues the meiotic deficits in oocytes from reproductive aged mice. In contrast, overexpression of acetylation-mimetic mutant H4K16Q abolishes the beneficial effects of melatonin on the meiotic phenotypes in aged oocytes. To sum up, our data uncover that melatonin alleviates advanced maternal aged-associated meiotic defects in oocytes through the SIRT2-depenendet H4K16 deacetylation pathway.
已有大量报道称，高龄产妇会损害卵母细胞质量。迄今为止，已经发现了多种参与这一过程的分子。然而，预防与年龄相关的生育问题仍然是一个挑战。在本研究中，我们发现补充和给予褪黑素均可缓解高龄卵母细胞的减数分裂表型，特别是纺锤体/染色体紊乱和非整倍体的产生。此外，我们确定 SIRT2 是介导褪黑素对老年卵母细胞减数分裂结构影响的关键效应因子。候选物筛选表明，SIRT2 控制的组蛋白 H4K16 去乙酰化对于维持卵母细胞中的减数分裂装置至关重要。重要的是，非乙酰化模拟突变体 H4K16R 部分挽救了生殖年龄小鼠卵母细胞中的减数分裂缺陷。相比之下，乙酰化模拟突变体 H4K16Q 的过表达则消除了褪黑素对高龄卵母细胞减数分裂表型的有益作用。总之，我们的数据揭示了褪黑素通过 SIRT2 依赖的 H4K16 去乙酰化途径缓解高龄产妇相关的卵母细胞减数分裂缺陷。
