Zygotic genome activation (ZGA)

Among the first loci to be transcribed is the DUX4 array of double-homeobox transcription factors. (DUX4 appears to be homologous in structure and function with Dux of mice.) DUX4 binds the promoters of ZGA-expressed genes such as ZSCAN4, DUXA, DUXB, LEUTX, and KDM4E and interacts with the Mediator complex to activate transcription (Vuoristo et al. 2022, reviewed in Kobayashi and Tachibana 2021).

DUX4 also binds long terminal repeats (LTRs) of thousands of endogenous retroelements, notably the HERVL family of retroelements, and activates bidirectional transcription that can initiate expression of adjacent genes (reviewed in Fu et al. 2019, Low et al. 2021). Interestingly, this transcription of endogenous retroviruses evidently results in production of retrovirus-like particles in the plasma and tissues of human embryos.

DUX4 binds HSATII pericentric satellite repeats and initiates bidirectional transcription. The transcripts appear to be required for subsequent formation of chromocenters, large multichromosome conglomerations of heterochromatin.

The minor ZGA is followed by the major ZGA at the 2-cell stage in mice and the 8-cell stage in humans. During the major ZGA, chromatin reverts to a more usual configuration, with broad regions of histone H3 trimethyllysine-4 across genes converted to narrow peaks near transcription start sites (reviewed in Eckersley-Maslin et al. 2018, Schulz and Harrison 2019, Wu and Vastenhouw 2020, Aoki 2022). Histones H3.1 and H3.2 are also added at this time.