Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, 210093, China.
Reprod Biol Endocrinol. 2023 Oct 31;21(1):103. doi: 10.1186/s12958-023-01147-w.
With advanced maternal age, abnormalities during oocyte meiosis increase significantly. Aneuploidy is an important reason for the reduction in the quality of aged oocytes. However, the molecular mechanism of aneuploidy in aged oocytes is far from understood. Histone acetyltransferase 1 (HAT1) has been reported to be essential for mammalian development and genome stability, and involved in multiple organ aging. Whether HAT1 is involved in ovarian aging and the detailed mechanisms remain to be elucidated.
The level of HAT1 in aged mice ovaries was detected by immunohistochemical and immunoblotting. To explore the function of HAT1 in the process of mouse oocyte maturation, we used Anacardic Acid (AA) and small interfering RNAs (siRNA) to culture cumulus-oocyte complexes (COCs) from ICR female mice in vitro and gathered statistics of germinal vesicle breakdown (GVBD), the first polar body extrusion (PBE), meiotic defects, aneuploidy, 2-cell embryos formation, and blastocyst formation rate. Moreover, the human granulosa cell (GC)-like line KGN cells were used to investigate the mechanisms of HAT1 in this progress.
HAT1 was highly expressed in ovarian granulosa cells (GCs) from young mice and the expression of HAT1 was significantly decreased in aged GCs. AA and siRNAs mediated inhibition of HAT1 in GCs decreased the PBE rate, and increased meiotic defects and aneuploidy in oocytes. Further studies showed that HAT1 could acetylate Forkhead box transcription factor O1 (FoxO1), leading to the translocation of FoxO1 into the nucleus. Resultantly, the translocation of acetylated FoxO1 increased the expression of amphiregulin (AREG) in GCs, which plays a significant role in oocyte meiosis.
The present study suggests that decreased expression of HAT1 in GCs is a potential reason corresponding to oocyte age-related meiotic defects and provides a potential therapeutic target for clinical intervention to reduce aneuploid oocytes.
随着产妇年龄的增长，卵母细胞减数分裂过程中的异常显著增加。非整倍体是高龄卵母细胞质量下降的一个重要原因。然而，高龄卵母细胞非整倍体的分子机制还远未被理解。组蛋白乙酰转移酶 1（HAT1）已被报道对哺乳动物的发育和基因组稳定性至关重要，并参与多个器官的衰老。HAT1 是否参与卵巢衰老以及详细的机制仍有待阐明。
通过免疫组织化学和免疫印迹检测衰老小鼠卵巢中 HAT1 的水平。为了探讨 HAT1 在小鼠卵母细胞成熟过程中的作用，我们使用 Anacardic Acid（AA）和小干扰 RNA（siRNA）在体外培养 ICR 雌性小鼠的卵丘-卵母细胞复合物（COC），并对生发泡破裂（GVBD）、第一极体排出（PBE）、减数分裂缺陷、非整倍体、2 细胞胚胎形成和囊胚形成率进行统计。此外，还使用人卵巢颗粒细胞（GC）样细胞系 KGN 细胞来研究 HAT1 在这一过程中的作用机制。
HAT1 在年轻小鼠的卵巢颗粒细胞（GC）中高表达，而在衰老 GC 中的表达显著降低。AA 和 siRNA 介导的 HAT1 在 GC 中的抑制降低了 PBE 率，并增加了卵母细胞的减数分裂缺陷和非整倍体。进一步的研究表明，HAT1 可以乙酰化叉头框转录因子 O1（FoxO1），导致 FoxO1 转位到细胞核内。结果，乙酰化 FoxO1 的转位增加了 GC 中 Amphiregulin（AREG）的表达，AREG 在卵母细胞减数分裂中起着重要作用。
本研究表明，GC 中 HAT1 的表达降低是卵母细胞与年龄相关的减数分裂缺陷的一个潜在原因，并为临床干预减少非整倍体卵母细胞提供了一个潜在的治疗靶点。
