开启生命程序:合子基因组如何启动?

Kickstarting the program of the life:How is the zygotic genome activated?

合子基因组激活(zygotic genome activation,ZGA)是卵子受精后的第一个转录事件,标志着胚胎基因表达程序的启动.ZGA缺陷严重影响胚胎发育,甚至导致胚胎死亡.随着微量细胞测序技术和单细胞分析技术的快速发展,人们对ZGA的理解在近年来取得了长足进步.相关研究揭示了ZGA期间表观基因组、转录组、蛋白质组和代谢组的景观、重编程过程和相关机制.此外,ZGA的正常启动依赖多方面因素的协同调控.表观遗传重编程为ZGA及后续转录过程建立适宜的染色质环境,ZGA也影响表观遗传的重编程.ZGA也广泛受到RNA水平的调控,关键转录因子通过选择性激活基因表达驱动ZGA发生.本综述阐述了不同物种ZGA相关表观遗传重编程事件,ZGA相关RNA调控因子、核心ZGA转录因子的作用机制,以及ZGA期间转录组、蛋白质组、代谢组等多维度重编程景观.最后,我们针对ZGA过程中尚未解决的科学问题进行了深入探讨.

In all species studied so far,the zygotic genome undergoes a period of transcriptional silence after fertilization.Zygotic genome activation(ZGA)is the first transcriptional event post-fertilization,marking the onset of the embryonic gene expression program and the establishment of totipotency.Defects in ZGA usually severely impact embryonic development,even leading to lethality.The exact timing of ZGA and the biological events during this period vary among species.Due to the scarcity of early embryo materials,the mechanisms underlying ZGA have historically been difficult to elucidate.With the rapid development of low-input and single-cell analysis technologies,our understanding of ZGA has significantly advanced in recent years.Studies have revealed the dynamic landscapes of the epigenome,transcriptome,proteome,and metabolome during ZGA.Activating chromatin modifications,such as H3K27ac and H3K4me3,and repressive chromatin modifications,such as DNA methylation,H3K9me3,H3K27me3,and H2AK119ub,undergo dramatic reprogramming in early mammalian embryos to accommodate active transcription during ZGA.Histone variants,such as H3.3 and H2A.Z,also participate in gene regulation and epigenetic reprogramming in early development.The widely relaxed higher-order chromatin structure following fertilization is a hallmark of early embryo,providing a unique environment for gene expression.Multi-level RNA regulation,such as RNA modification,splicing regulation and translational regulation,plays crucial roles in gene expression regulation.Transposable elements,such as MERVL and LINE,are massively activated during early stages of mammalian embryonic development,influencing gene expression regulation and epigenetic reprogramming.Key transcription factors,either deposited by oocytes or transcribed at the early phase of ZGA,function as“specifiers”to drive the onset of ZGA by activating the expression of selected targets.Reprogramming of the proteome also differs substantially from those of the transcriptome and translatome,suggesting extensive post-translational regulation.Metabolites also influence ZGA by participating in epigenetic reprogramming,which is a fast-developing research direction.Despite the exciting progress in unveiling the molecular principles underlying ZGA,many critical questions regarding ZGA remain unanswered.For example,what determines the timing of ZGA across species?How are some epigenetic marks at specific sites retained during epigenetic reprogramming and inherited across generations?What are the upstream factors that prime ZGA?How do epigenetic factors and transcription factors crosstalk during ZGA?Why have ZGA transcription factors diverged significantly across species during evolution?On the other hand,the scarcity of samples is a major obstacle in early embryo research.The development of low-input and single-cell analysis technologies remains crucial for the field.The establishment of appropriate in vitro ZGA systems,such as 2C-like cells and 8C-like cells,is also essential for dissecting the molecular circuitry governing ZGA.In this review,we will first summarize the current progress in understanding the epigenetic reprogramming events during ZGA in different species.We will also review the key factors controlling the timing and specificity of ZGA,and the multi-dimensional molecular reprogramming in ZGA.Finally,we will discuss the key unresolved questions in the field of ZGA research that await answers.