Abstract
BackgroundInvestigating how epigenetic information is transmitted through the mammalian germline is the key to understanding how this information impacts on health and disease susceptibility in offspring. EED is essential for regulating the repressive histone modification, histone 3 lysine 27 tri-methylation (H3K27me3) at many developmental genes.ResultsIn this study, we used oocyte-specific Zp3-Cre recombinase (Zp3Cre) to delete Eed specifically in mouse growing oocytes, permitting the study of EED function in oocytes and the impact of depleting EED in oocytes on outcomes in offspring. As EED deletion occurred only in growing oocytes and females were mated to normal wild type males, this model allowed the study of oocyte programming without confounding factors such as altered in utero environment. Loss of EED from growing oocytes resulted in a significant overgrowth phenotype that persisted into adult life. Significantly, this involved increased adiposity (total fat) and bone mineral density in offspring. Similar overgrowth occurs in humans with Cohen-Gibson (OMIM 617561) and Weaver (OMIM 277590) syndromes, that result from de novo germline mutations in EED or its co-factor EZH2, respectively. Consistent with a role for EZH2 in human oocytes, we demonstrate that de novo germline mutations in EZH2 occurred in the maternal germline in some cases of Weaver syndrome. However, deletion of Ezh2 in mouse oocytes resulted in a distinct phenotype compared to that resulting from oocyte-specific deletion of Eed.ConclusionsThis study provides novel evidence that altering EED-dependent oocyte programming leads to compromised offspring growth and development in the next generation.
Highlights
Investigating how epigenetic information is transmitted through the mammalian germline is the key to understanding how this information impacts on health and disease susceptibility in offspring
We used a Zona Pellucida 3 (Zp3)-Cre recombinase (Zp3Cre) transgene to mediate oocyte-specific deletion of Eed, in order to determine the effect loss of maternal polycomb repressive complex 2 (PRC2) function had on offspring (Fig. 1a)
Genotyping of progeny from Eed floxed females carrying Zp3Cre mated to wild type males demonstrated that Eed deletion was 100% efficient in oocytes (Additional file 1: Figure S1; Chisquare test, nsd)
Summary
Investigating how epigenetic information is transmitted through the mammalian germline is the key to understanding how this information impacts on health and disease susceptibility in offspring. Factors regulating oocyte (egg) and sperm programming and early embryonic development have been associated with the fetal origins of disease, including reduced cognitive ability and increased chronic diseases, such as type-2 diabetes, obesity, heart disease and behavioural anomalies [1,2,3,4,5]. The causes of these defects are poorly understood, but are likely to be in part due to altered epigenetic programming of oocytes or sperm that significantly impact on embryonic development and underlie the fetal origin of some of these disorders [1, 2, 4].
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