Figure 7. S1/S2 compartments are transitional states during XCI.

(A) Allele-specific Hi-C analysis: Top: Contact maps (200-kb resolution) of the Xi (X^mus) in undifferentiated ES cells (D0 ES, pre-XCI), embryoid bodies after 4 or 7 differentiation days (D4 and D7 EB, early-mid XCI), and WT and Smchd1^-/- NPCs (post-XCI). Bottom: Pearson correlation maps.

(B) PCA of the D0 Xa (comp), the Xi (X^mus) at different stages of XCI, and correlation with Xist spreading patterns (GSE48649). D3 Xist patterns represent “early domains.” Blue and red arrows indicate fusion of consecutive A/B compartments to form S1/S2.

(C) The Origami Model for step-wise Xi folding. Xist RNA is produced from A compartment and initially spreads to co-segregated A compartments (red) through proximity transfer. Xist fuses A/B into S1/S2 compartments, correlating with the two-step Xist spreading into early (gene-rich), then late (gene-poor) domains (Simon et al., 2013). Following SMCHD1 recruitment, S1/S2 compartments are merged (top) to form a compartmentless structure. In Smchd1^-/- cells, the final transformation does not occur and S1/S2 compartments persist (bottom), resulting in defective Xist spreading and gene silencing.

(D) Model: SMCHD1 bridges Xist-rich and Xist-poor chromatin to promote chromatin mixing and merging of S1/S2 compartments (left). Without SMCHD1, Xist-rich chromatin co-segregates, leading to the formation of S1/S2 compartments (right).