Comparison of epigenetic mediator expression and function in mouse and human embryonic blastomeres

Abstract

A map of human embryo development that combines imaging, molecular, genetic and epigenetic data for comparisons to other species and across pathologies would be greatly beneficial for basic science and clinical applications. Here, we compared mRNA and protein expression of key mediators of DNA methylation and histone modifications between mouse and human embryos, embryos from fertile/infertile couples, and following growth factor supplementation. We observed that individual mouse and human embryos are characterized by similarities and distinct differences in DNA methylation and histone modification patterns especially at the single-cell level. In particular, while mouse embryos first exhibited sub-compartmentalization of different histone modifications between blastomeres at the morula stage and cell sub-populations in blastocysts, differential histone modification expression was detected between blastomeres earlier in human embryos at the four- to eight-cell stage. Likewise, differences in epigenetic mediator expression were also observed between embryos from fertile and infertile couples, which were largely equalized in response to growth factor supplementation, suggesting that select growth factors might prevent alterations in epigenetic profiles during prolonged embryo culture. Finally, we determined that reduced expression via morpholino technologies of a single histone-modifying enzyme, Rps6ka4/Msk2, resulted in cleavage-stage arrest as assessed by time-lapse imaging and was associated with aneuploidy generation. Taken together, data document differences in epigenetic patterns between species with implications for fertility and suggest functional roles for individual epigenetic factors during pre-implantation development.

Environmental factors, epigenetics, and developmental origin of reproductive disorders

“…Increasing challenges are anticipated in establishing transgenerational epigenetic inheritance in humans. Differences in epigenomes between mice and humans may not allow a direct extrapolation of data from mouse models [207]. Additionally, genetics may contribute to changing the epigenetic landscape through multiple human generations [207].…”

“…Differences in epigenomes between mice and humans may not allow a direct extrapolation of data from mouse models [207]. Additionally, genetics may contribute to changing the epigenetic landscape through multiple human generations [207]. Therefore, genetic variations in human populations will always be confounding factor for studying transgenerational epigenetic inheritance in humans [206].…”

Chromosomal instability in mammalian pre-implantation embryos: potential causes, detection methods, and clinical consequences

“…However, a recent study indicates that the formation of micro- and multiple-nuclei (multi-nuclei) can be induced in mouse embryos by disrupting the function of particular cell cycle proteins critical for developmental progression. Chavez and colleagues (2014) determined that translational block of Rps6ka4/Msk2 , a mitogenic factor known to be involved in the G1 phase of the cell cycle (Bettencourt-Dias et al 2004), in mouse zygotes resulted in the appearance of multiple micro- or multi-nuclei at the cleavage stage. In addition, increased blastomere movement and lysis, resembling cellular events described during mitotic catastrophe (Vakifahmetoglu et al 2008), was also observed in mouse embryos following mitotic arrest at the 3- to 8-cell stage.…”

Genetics and epigenetics of circadian rhythms and their potential roles in neuropsychiatric disorders

“…Most studies have been performed in mouse models, and only a few in humans. Since differences in epigenetic regulation between mice and humans during pre-implantation development have been observed [141] , findings from mice and other species may not translate to humans directly. Moreover, many epigenetic factors, such as hydroxymethylation, long non-coding RNAs, and most of the histone modifications other than acetylation, have not been studied in the context of circadian regulation in humans.…”