Zygotic gene activation in mice: profile and regulation

Abstract

The zygotic genome is transcriptionally silent immediately after fertilization. In mice, initial activation of the zygotic genome occurs in the middle of the one-cell stage. At the mid-to-late two-cell stage, a burst of gene activation occurs after the second round of DNA replication, and the profile of transcribed genes changes dramatically. These two phases of gene activation are called minor and major zygotic gene activation (ZGA), respectively. As they mark the beginning of the gene expression program, it is important to elucidate gene expression regulation during these stages. This article reviews the outcomes of studies that have clarified the profiles and regulatory mechanisms of ZGA.

Keywords: Chromatin structure; Epigenetic factors; Preimplantation development; Zygotic gene activation.

Fig. 1.

Zygotic gene activation (ZGA) in mice. The zygotic genome is transcriptionally inert immediately after fertilization and is activated at the mid-S phase of the one-cell stage. The gene expression pattern changes dramatically during the second round of DNA replication. Genome activation before and after DNA replication is called minor and major ZGA, respectively. Transcribed mRNAs that accumulate during oocyte growth (maternal RNA) remain after fertilization to support development until major ZGA occurs.

Fig. 2.

Change in the regulatory mechanism of gene expression during minor and major ZGA. In one-cell- and early two-cell-stage embryos (during minor ZGA), chromatin structure is loosened because the nucleosome contains a unique combination of histone variants (H3.3/H2A.X, TH2A). This type of chromatin structure appears to allow transcription with GC box-like motifs as promoters, causing global, promiscuous expression from the genome, including intergenic regions. However, at the late two-cell stage (during major ZGA), a core promoter and enhancers are required for active transcription, as occurs in most cell types, due to the tight chromatin structure, which contains all the histone variants.

Fig. 3.

Involvement of Dux in the transition from minor to major ZGA. In oocytes, tandem repeats of Dux and its paralogs (Dux family genes) form transcriptionally silent heterochromatin. However, their chromatin structures become loosened in one-cell stage embryos, inducing transcription of numerous Dux family genes. In these embryos, the transcripts of most genes do not produce functional proteins due to inefficient splicing. However, functional proteins are translated from Dux transcripts because Dux is an intronless gene. The DUX protein activates major ZGA genes until its elimination at the late two-cell stage when the chromatin structure tightens.