EED mediates epigenetic repression of developmental genes in growing oocytes and modulates neural and skeletal development in offspring [Bone Samples]

Epigenetic modifications regulate transcriptional access to unique cell-type-specific gene sets, which define cell differentiation and tissue development. Cell-to-cell heritability of this information provides long-term molecular memories that define cell lineage identities. Germline epigenetic programming, including genomic imprinting, can substantially alter offspring development, but the mechanisms are poorly understood. In this study we demonstrate that the essential polycomb complex gene, Eed, regulates histone methylation in a large cohort of non-imprinted developmental genes in mouse and human oocytes. Using a model that facilitates the separation of genetic and epigenetic inheritance, we show that Eed establishes H3K27me3 during a unique widow of early oocyte growth and is essential in mouse oocytes for mediating a complex program that controls fetal growth and co-ordinated development of multiple tissues in late-stage fetal offspring, including bone, brain and placenta. Our study defines a new role for Eed in epigenetic inheritance that profoundly affects offspring growth and development. Examination of the impact of EED deletion in oocytes on oocyte epigenetic programming and offspring development表观遗传修饰（epigenetic modifications）可调控细胞类型特异性基因集的转录可及性，而该过程决定细胞分化与组织发育。此类信息的细胞间遗传性可形成长期分子记忆，进而界定细胞谱系身份。生殖系表观遗传编程（germline epigenetic programming）——包括基因组印记（genomic imprinting）——可显著改变子代发育，但其具体机制迄今尚不明确。本研究证实，核心多梳复合体基因Eed可在小鼠与人类卵母细胞中，调控大量非印记发育基因的组蛋白甲基化（histone methylation）。我们借助可分离遗传与表观遗传的实验模型，发现Eed于卵母细胞早期生长的独特窗口期建立H3K27me3修饰，且对小鼠卵母细胞介导复杂发育程序至关重要：该程序可调控晚期胎仔的胎儿生长，以及骨骼、大脑与胎盘等多种组织的协调发育。本研究明确了Eed在表观遗传继承中发挥的全新功能，其可深刻影响子代的生长与发育。本研究还检测了卵母细胞中EED敲除对卵母细胞表观遗传编程及子代发育的影响。