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. 2022 Nov 1;12(11):1611. doi: 10.3390/biom12111611

Figure 1.

Figure 1

Scheme of cell fate conversion via rRNA biogenesis. In the mature nucleoli of embryonic stem cells (ESCs), high-abundance rRNA maintains nucleolar liquid–liquid phase separation (LLPS) and integrity, thus facilitating nucleolin (NCL)/tripartite motif-containing 28 (TRIM28) complex occupancy on DUX loci, causing DUX repression in perinucleolar heterochromatin. ESCs do not display transcriptome features similar to those of 2-cell-stage embryos, especially without DUX activation. In contrast, in the disrupted nucleolus of 2-cell-like cells (2CLCs), adding CX-5461 inhibits the recruitment of the selective factor 1 (SL-1) complex and polymerase I (Pol I) initiation factor to rDNA, thus impairing rRNA synthesis. The inhibition of rRNA synthesis interferes with nucleolar LLPS and then disrupts nucleolar integrity and causes dissociation of the NCL/TRIM28 complex from DUX loci, providing a permissive environment for DUX derepression. Furthermore, DUX functions as a core transcription factor for zygotic genome activation (ZGA) and drives the expression of MERVL and 2-cell-specific genes (e.g., Zscan4), which allow 2CLCs to obtain transcriptome features that resemble those of 2-cell-stage embryos.