The Dynamics of Histone Modifications during Mammalian Zygotic Genome Activation

Abstract

Mammalian fertilization initiates the reprogramming of oocytes and sperm, forming a totipotent zygote. During this intricate process, the zygotic genome undergoes a maternal-to-zygotic transition (MZT) and subsequent zygotic genome activation (ZGA), marking the initiation of transcriptional control and gene expression post-fertilization. Histone modifications are pivotal in shaping cellular identity and gene expression in many mammals. Recent advances in chromatin analysis have enabled detailed explorations of histone modifications during ZGA. This review delves into conserved and unique regulatory strategies, providing essential insights into the dynamic changes in histone modifications and their variants during ZGA in mammals. The objective is to explore recent advancements in leading mechanisms related to histone modifications governing this embryonic development phase in depth. These considerations will be useful for informing future therapeutic approaches that target epigenetic regulation in diverse biological contexts. It will also contribute to the extensive areas of evolutionary and developmental biology and possibly lay the foundation for future research and discussion on this seminal topic.

Keywords: chromatin landscape; embryonic development; embryonic stem cells; histone modifications; mammals.

Figure 1

Epigenetic dynamics of H3K4me3 and H3K9me3 in early mouse embryogenesis. (A) H3K4me3 experiences swift depletion in the paternal genome post-fertilization, only to be reinstated during ZGA. Conversely, the deposition of ncH3K4me3 coincides with the silencing of the genome originating from fully grown oocytes and is subsequently substituted by canonical H3K4me3 at the 2-cell stage. Throughout ZGA, chromatin accessibility becomes evident at the H3K4me3-marked TSS sites of active genes. Simultaneously, transposable elements exhibit enrichment in H3K4me3. Progressing through development, there is a gradual escalation of H3K4me3 marks, culminating in forming a bivalent state with H3K27me3, priming the activation of developmental genes during the blastocyst stage. (B) Maternal genome-specific regions with H3K9me3 marks are more prevalent than paternal genome regions during early embryogenesis. The onset of early embryonic development triggers extensive DNA demethylation, resulting in the hypomethylation of actively transcribed regions, including LTRs. After fertilization, H3K9me3 marks within LTRs gradually increase during pre-implantation development. The majority of parental H3K9me3 regions are established de novo after fertilization. H3K9me3-enriched LTRs progressively emerge after the 4-cell stage and play a role in LTR silencing. Additionally, H3K9me3 marks in the promoters of developmental genes are erased after fertilization and restored after implantation. Abbreviations: LTRs, long terminal repeats; MZT, Maternal-to-zygotic transition; TEs, transposable elements; TSS, transcriptional start sites; ZGA, zygotic genome activation. Created with www.biorender.com (accessed on 25 December 2023).

Figure 2

Antagonistic activity between H3K27me3 and H3K27ac in ZGA gene expression. (A) A polycomb repressive complex (PRC2) orchestrates the trimethylation of histone 3 on lysine 27 via histone methyltransferase activity. The SAM cofactor in Enhancer of zeste homolog 2 (EZH2), one of the PCR2 subunits, is essential to recognize the H3K27 tail selectively. The introduction of the trimethylation mark on lysine residue located at position 27 of the histone H3 tail results in the downregulation of nearby genes by forming heterochromatic regions. H3K27me3 experiences widespread loss in promoter regions at the 2-cell stage while manifesting in non-promoter regions in a highly pervasive manner. (B) A HAT facilitates the acetylation of histone 3 on lysine 27 by transferring an acetyl group from acetyl CoA. H3K27ac is an active enhancer mark, promoting a more accessible chromatin structure. It is present in both distal and proximal regions of genes, with enrichment observed at TSS. The H3K27ac marks exhibit discernible intensity in zygotes, 2-cell, and 4-cell embryos but gradually decline in 8-cell embryos. Abbreviations: Ac, acetylation; HAT, histone acetyltransferase; Me, methylation; PRC2, Polycomb Repressive Complex 2; RNAPII, RNA polymerase II; SAM, S-adenosylmethionine; TSS, transcriptional start sites. Created with Created with www.biorender.com (accessed on 25 December 2023).