Fig. 10: A mechanistic model for the role of rRNA biogenesis in regulating mouse 2C-like state.

In the unperturbed mES cells, nucleolar integrity mediated by rRNA biogenesis maintains the normal liquid-liquid phase separation (LLPS) of nucleolus and the formation of peri-nucleolar heterochromatin (PNH) containing Dux, and this normal nucleolar LLPS facilitates NCL/TRIM28 complex occupancy on the Dux locus and repression of Dux expression. In contrast, in the rRNA biogenesis-inhibited mES cells, the natural liquid-like phase of nucleolus is disrupted, causing dissociation of the NCL/TRIM28 complex from PNH and changes of epigenetic state and 3D structure of PNH, which eventually leads to Dux released from PNH, activation of 2C-like program and transition of mES cells to 2C-like cells.