SummaryVertebrate eggs can induce the nuclear reprogramming of somatic cells to enable production of cloned animals. Nuclear reprogramming is relatively inefficient, and the development of the resultant embryos is frequently compromised, in part due to the inappropriate expression of genes previously active in the donor nucleus. Here, we identify H3K4 methylation as a major epigenetic roadblock that limits transcriptional reprogramming and efficient nuclear transfer (NT). Widespread expression of donor-cell-specific genes was observed in inappropriate cell types in NT embryos, limiting their developmental capacity. The expression of these genes in reprogrammed embryos arises from epigenetic memories of a previously active transcriptional state in donor cells that is characterized by high H3K4 methylation. Reducing H3K4 methylation had little effect on gene expression in donor cells, but it substantially improved transcriptional reprogramming and development of NT embryos. These results show that H3K4 methylation imposes a barrier to efficient nuclear reprogramming and suggest approaches for improving reprogramming strategies.

Mitotic divisions result from the oscillating activity of cyclin-dependent kinase 1 (Cdk1). Cdk1 activity is terminated by the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that targets cyclin B for destruction. In somatic divisions, the early mitotic inhibitor 1 (Emi1) and the spindle assembly checkpoint (SAC) regulate cell cycle progression by inhibiting the APC/C. Early embryonic divisions lack these APC/C-inhibitory components, which raises the question of how those cycles are controlled. We found that the APC/C-inhibitory activity of XErp1 (also known as Emi2) was essential for early divisions in Xenopus embryos. Loss of XErp1 resulted in untimely destruction of APC/C substrates and embryonic lethality. XErp1's APC/C-inhibitory function was negatively regulated by Cdk1 and positively by protein phosphatase 2A (PP2A). Thus, Cdk1 and PP2A operate at the core of early mitotic cell cycles by antagonistically controlling XErp1 activity, which results in oscillating APC/C activity.

Ex ovo omnia-all animals come from eggs-this statement made in 1651 by the English physician William Harvey marks a seminal break with the doctrine that all essential characteristics of offspring are contributed by their fathers, while mothers contribute only a material substrate. More than 360 years later, we now have a comprehensive understanding of how haploid gametes are generated during meiosis to allow the formation of diploid offspring when sperm and egg cells fuse. In most species, immature oocytes are arrested in prophase I and this arrest is maintained for few days (fruit flies) or for decades (humans). After completion of the first meiotic division, most vertebrate eggs arrest again at metaphase of meiosis II. Upon fertilization, this second meiotic arrest point is released and embryos enter highly specialized early embryonic divisions. In this review, we discuss how the standard somatic cell cycle is modulated to meet the specific requirements of different developmental stages. Specifically, we focus on cell cycle regulation in mature vertebrate eggs arrested at metaphase II (MII-arrest), the first mitotic cell cycle, and early embryonic divisions.