The progression from the one-cell to the two-cell stage constitutes a remarkable transition, accompanied by the activation of a specific set of embryonic genes, epigenome reprogramming and nuclear architecture reorganization. Some of these characteristics are recapitulated in vitro with the spontaneous emergence of two-cell-like cells from mouse embryonic stem cells, which exhibit a transcriptomic signature resembling the two-cell stage, including the expression of genes such as Dux , Zscan4 and the repetitive element MERVL , as well as a more relaxed chromatin state. Here we show that interchromosomal and intrachromosomal interactions driven by Zscan4 chromatin factors form during this transition and segregate into a distinct genomic compartment, the Z compartment, independently of cohesin and CCCTC-binding factor. Mechanistically, the formation of Z-DNA, an alternative DNA conformation regulated by polyamine levels, appears to promote the emergence of totipotent-like cells and the establishment of the Z compartment. This compartment is characterized by a decrease in active histone marks and a reduced expression of genes associated with differentiation and late developmental processes. Overall, these findings suggest that Z-DNA formation may have a dual role, first in initiating zygotic genome activation (ZGA) and later in guiding genome compartmentalization to safeguard the totipotent-like state by restricting the expression of non-ZGA genes within a permissive chromatin environment.
Shajahan et al. (Tue,) studied this question.