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bioRxiv · 10.1101/2021.10.28.466222

Maternal Ezh1/2 deficiency in oocyte delays H3K27me2/3 restoration and impairs epiblast development responsible for embryonic sub-lethality in mouse

Zhao, Y.·Zhang, D.·Liu, M.·Tian, Y.·Lu, J.·Gao, S.·Wang, H.-B.·Lu, Z.
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Abstract

Mammalian embryonic development is a complex process regulated by various epigenetic modifications. Recently, maternal histone H3 methylations were found to be inherited and reprogrammed in early embryos to regulate embryonic development. The enhancer of zest homolog 1 and 2 (Ezh1 and Ezh2) belong to the core components of Polycomb repressive complex 2 (PRC2) and are the histone methyltransferase of histone 3 lysine 27 (H3K27). How maternal Ezh1 and Ezh2 function on H3K27 methylation in in vivo preimplantation embryos and embryonic development are not clear. Here, we deleted Ezh1 or/and Ezh2 in growing oocytes using gene knockout mouse models, and found that H3K27me3 in oocytes was disappeared by loss of Ezh2 alone while H3K27me2 was absent upon deletion of both Ezh1 and Ezh2. The effects of Ezh1/2 were inherited in maternal knockout zygotes and early embryos, in which restoration of H3K27me3 was delayed until late blastocyte by loss of Ezh2 alone and H3K27me2 was reestablished until morulae by deletion of Ezh1 and Ezh2. However, the ablation of both Ezh1 and Ezh2, but not single Ezh1 or Ezh2, led to significantly decreased litter size due to growth retardation during post-implantation. Furthermore, maternal Ezh1/2 deficiency caused compromised H3K27me3 and pluripotent epiblast cells in late blastocyst, followed by defective development of epiblast. These results demonstrate that in oocytes, Ezh2 is indispensable for H3K27me3 while Ezh1 complements Ezh2 in H3K27me2. Also, maternal Ezh1/2-H3K27 methylation is inherited in descendant embryos and has a critical effect on fetus and placenta development. Thus, this work sheds light on maternal epigenetic modifications during embryonic development.

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Zhao, Y., Zhang, D., Liu, M., Tian, Y., Lu, J., Gao, S., Wang, H.-B., Lu, Z.. 2021-10-28. Maternal Ezh1/2 deficiency in oocyte delays H3K27me2/3 restoration and impairs epiblast development responsible for embryonic sub-lethality in mouse. https://doi.org/10.1101/2021.10.28.466222

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