Z-DNA formation induces the totipotent-like state and primes Zscan4-dependent chromatin compartmentalization

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Abstract
A remarkable transition during murine development is the progression from the 1-cell embryo to the 2-cell stage, 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 2-cell-like cells from mouse embryonic stem cells, which exhibit a transcriptomic signature resembling the 2-cell stage, including the expression of genes such as Dux , Zscan4 , and the repetitive element MERVL , and a more relaxed chromatin state. Here, we show that inter- and intra-chromosomal interactions, driven by Zscan4 chromatin factors, form during this transition and segregate into a distinct genomic compartment (Z compartment). Mechanistically, the formation of Z-DNA, an alternative DNA conformation regulated by polyamine levels, promotes 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 play a dual role, first in activating ZGA genes 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.

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