Inadequate histone deacetylation during oocyte meiosis causes aneuploidy and embryo death in mice

Abstract

Errors in meiotic chromosome segregation are the leading cause of spontaneous abortions and birth defects. Almost all such aneuploidy derives from meiotic errors in females, with increasing maternal age representing a major risk factor. It was recently reported that histones are globally deacetylated in mammalian oocytes during meiosis but not mitosis. In the present study, inhibition of meiotic histone deacetylation was found to induce aneuploidy in fertilized mouse oocytes, which resulted in embryonic death in utero at an early stage of development. In addition, a histone remained acetylated in the oocytes of older (10-monthold) female mice, suggesting that the function for histone deacetylation is decreased in the oocytes of such mice. Thus, histone deacetylation may be involved in the fair distribution of chromosomes during meiotic division. The high incidence of aneuploidy in the embryos of older females may be due to inadequate meiotic histone deacetylation.acetylation ͉ meiotic maturation ͉ chromosome segregation

Epigenetic changes associated with oocyte aging

“…For mice, the above lysine residues on H3 and H4 are acetylated in GV oocytes. However, with the resumption of meiosis, deacetylation was observed in MII oocytes, with the exception of H4K8ac which was reported present or absent regarding acetylation [40,41]. For humans, H4K5, H4K8, H4K12 and H4K16 were acetylated in GV oocytes, while partial deacetylation in MII oocytes was shown [42].…”

“…Inadequate histone deacetylation during mouse oocyte meiosis may cause aneuploidy and embryo death. On the other hand, old mouse oocytes have higher levels of acetylation at H4K8 and H4K12 when compared to that of young oocytes [40]. Similar to old mouse oocytes, it has been reported that defective deacetylation of H4K12 in human oocytes is associated with advanced maternal age as well as chromosome misalignment [42].…”

“…The effects of increasing maternal aging on histone acetylation of oocytes were firstly reported by Akiyama et al [40], who compared the profiles of acetylation at various lysine residues on H4 using mouse oocytes from young (age 3 weeks) and old (age 10 months) BDF1 females. The authors revealed that H4K12 remained acetylated in 40% of the MII-stage oocytes of older mice, whereas histone deacetylation was complete in the oocytes of young mice.…”

“…Histone acetylation has been shown to be related to chromosome segregation [29]. On one hand, the presence of TSA in the medium during mammalian oocyte in vitro maturation resulted in hyperacetylation at some lysine residues and a high frequency of spindle defects and chromosome missegregation in mouse and porcine oocytes [40,54,55]. Inadequate histone deacetylation during mouse oocyte meiosis may cause aneuploidy and embryo death.…”

Dysregulation of methylation and expression of imprinted genes in oocytes and reproductive tissues in mice of advanced maternal age

“…Mice are generally retired from breeding around 9 months of age [27]; however, females are still capable of ovulating and carrying offspring, albeit at a lower frequency than their younger counterparts. Previous reports have been successful in stimulating and collecting metaphase II oocytes from mice ranging from 10 to 16 months of age [7,15,[28][29][30][31]. B6D2F1 mice are considered exceptional breeders, as females regularly produce large litters (JAX® Mice; Jackson Laboratory, Bar Harbor, ME) and have a long lifespan of approximately 26 months on average (Harlan Laboratories, Indianapolis, IN).…”