Year: 2024
Type: article
Abstract: 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.
DOI: 10.1360/tb-2024-0844
Authors: Zihan Xu, Feng Kong, Wei Xie
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4403259382