（通訊員 劉鑫 布國偉(wei) ）近日，我校動物科學技術學院、動物醫學院苗義(yi) 良教授動物克隆與(yu) 幹細胞研究團隊研究成果以“Coordination of zygotic genome activation entry and exit by H3K4me3 and H3K27me3 in porcine early embryos”在Genome Research發表。研究全麵揭示了H3K4me3和H3K27me3在豬卵母細胞和受精胚胎發育過程中的動態分布規律，並首次證實了H3K4me3和H3K27me3參與(yu) 調控豬受精胚胎合子基因組激活（ZGA）發生和退出的機製。
ZGA是動物早期胚胎發育過程中的核心事件，是實現母源-合子轉換的關(guan) 鍵，且不同物種ZGA的發生時期也有所不同。先前的研究已發現多個(ge) 基因調控該事件的發生，而組蛋白修飾在該過程中同樣發揮了重要的作用。
H3K4me3和H3K27me3在豬受精胚胎發育中的動態變化和功能研究
研究人員首先發現豬卵母細胞中的H3K4me3在ZGA基因啟動子處呈現窄峰，受精後轉變為(wei) 寬峰，4細胞期後又轉變為(wei) 窄峰。在受精卵中同時敲低KDM5B和KDM5C（H3K4去甲基化酶基因）可在ZGA基因啟動子上維持H3K4me3的寬峰分布，使ZGA基因無法激活表達，這說明H3K4me3在4細胞期的峰型轉換調控著ZGA發生。
其次，研究人員還發現桑椹胚期重新建立的H3K27me3也會(hui) 在ZGA基因啟動子處富集，並與(yu) H3K4me3形成二元共價(jia) 修飾。通過在胚胎培養(yang) 液中添加GSK126（EZH2抑製劑）阻斷H3K27me3的重建，發現ZGA基因在囊胚期的表達異常升高，這說明H3K4me3/H3K27me3共價(jia) 狀態在後期的建立有利於(yu) ZGA的退出。
最後，該團隊還分析了豬體(ti) 細胞克隆胚胎中H3K4me3和H3K27me3的分布情況，發現相比於(yu) 受精胚胎，兩(liang) 種修飾在克隆胚胎4細胞期均存在嚴(yan) 重的異常富集，而在囊胚期的富集差異較小，表明ZGA階段組蛋白修飾的異常重編程仍是影響豬克隆胚胎發育的關(guan) 鍵因素。
我校動物科學技術學院、動物醫學院苗義(yi) 良教授為(wei) 論文的通訊作者，布國偉(wei) 博士生、祝為(wei) 博士後和劉鑫副研究員為(wei) 論文的共同第一作者。該研究受到國家重點研發計劃、國家自然科學基金、湖北省重點研發計劃、湖北洪山實驗室項目、華中農(nong) 大校創基金等項目的資助。
【英文摘要】
Histone modifications are critical epigenetic indicators of chromatin state associated with gene expression. Although the reprogramming patterns of H3K4me3 and H3K27me3 have been elucidated in mouse and human preimplantation embryos, the relationship between these marks and zygotic genome activation (ZGA) remains poorly understood. By ultra-low-input native chromatin immunoprecipitation and sequencing, we profiled global H3K4me3 and H3K27me3 in porcine oocytes and in vitro fertilized (IVF) embryos. We found that promoters of ZGA genes occupied sharp H3K4me3 peaks in oocytes, and these peaks became broader after fertilization, and reshaped into sharp again during ZGA. By simultaneous depletion of H3K4me3 demethylase KDM5B and KDM5C, we determined that broad H3K4me3 domain maintenance impaired ZGA gene expression, suggesting its function to prevent premature ZGA entry. By contrast, broad H3K27me3 domains underwent global removal upon fertilization, followed by a re-establishment for H3K4me3/H3K27me3 bivalency in morulae. We also found that bivalent marks were deposited at promoters of ZGA genes, and inhibiting this deposition was correlated with the activation of ZGA genes. It suggests that promoter bivalency contributes to ZGA exit in porcine embryos. Moreover, we demonstrated that aberrant reprogramming of H3K4me3 and H3K27me3 triggered ZGA dysregulation in somatic cell nuclear transfer (SCNT) embryos, whereas H3K27me3-mediated imprinting did not exist in porcine IVF and SCNT embryos. Our findings highlight two previously unknown epigenetic reprogramming modes coordinated with ZGA in porcine preimplantation embryos. Finally, the similarities observed between porcine and human histone modification dynamics suggest that the porcine embryo may also be a useful model for human embryo research.
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