Institute of Biomedical Research, Yunnan University, Kunming 650500, China.
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Proc Natl Acad Sci U S A. 2024 Nov 19;121(47):e2410261121. doi: 10.1073/pnas.2410261121. Epub 2024 Nov 14.
Early embryos undergo profound changes in their genomic architecture to establish the totipotent state, enabling pioneer factors to access chromatin and drive zygotic genome activation (ZGA). However, the mechanisms by which the totipotent state is established and properly interpreted by pioneer factors to allow orderly ZGA remain unknown. Here, we identify the H3.3-specific chaperone HIRA as a factor involving establishing totipotent-state chromatin in early embryos. Through cophase separation with HIRA, the pioneer factor GAGA factor (GAF) efficiently binds to H3.3-marked nucleosomes to activate major-wave zygotic genes. Importantly, dPCIF1, a chromatin-associated protein, antagonized the GAF-HIRA interaction by competitively binding to HIRA, thereby restricting GAF on earlier chromatin and avoiding premature ZGA. Hence, the coordinated action of HIRA and dPCIF1 ensures sequential ZGA from the minor to major wave in early embryos. This study provides insights into understanding how a totipotent state is established and properly controlled during ZGA.
早期胚胎在其基因组结构上经历深刻变化，以建立全能性状态，使先驱因子能够接触染色质并驱动合子基因组激活（ZGA）。然而，建立全能性状态的机制以及先驱因子如何正确解释以允许有序的 ZGA 仍然未知。在这里，我们确定 H3.3 特异性伴侣 HIRA 作为一个因素，涉及早期胚胎中全能性染色质的建立。通过与 HIRA 的共相位分离，先驱因子 GAGA 因子（GAF）有效地结合到 H3.3 标记的核小体上，激活主要波合子基因。重要的是，染色质相关蛋白 dPCIF1 通过竞争性结合 HIRA 拮抗 GAF-HIRA 相互作用，从而将 GAF 限制在早期染色质上，并避免过早的 ZGA。因此，HIRA 和 dPCIF1 的协调作用确保了早期胚胎中从小波到大波的顺序 ZGA。本研究深入了解了在 ZGA 过程中如何建立和正确控制全能性状态。
