Fig. 8

A model for the folding and unfolding of the inactive X chromosome (Xi) origami. a Summary: A stepwise folding process for the transformation of the Xi (“Origami Model”). Xist RNA is produced from the A compartment. Following transcription, Xist initially spreads to co-segregated A-compartmental chromatin. Through recruiting polycomb repressive complex 1 (PRC1), Xist reconfigures the Xi into S1/S2 compartments. Following structural maintenance of chromosomes hinge domain containing 1 (SMCHD1) recruitment (via a mechanism requiring heterogeneous nuclear ribonucleoprotein K (HNRNPK), PRC1, and H2AK119ub), S1/S2 compartments are merged to form a compartment-less structure. In cells losing SMCHD1 after completing XCI, S1/S2 compartments reappear, coinciding with accumulation of Xist, H3K27me3, and H2AK119ub in the S1 compartment and destabilized gene silencing. Depleting PRC1 or HNRNPK diminishes the reappeared S1/S2 compartments, resulting in a “de-compartmentalized” Xi with sharper partition between the two megadomains. In cells that have undergone Xist ablation post XCI, both SMCHD1 and PRC1 fail to be recruited to the Xi, also leading to a “de-compartmentalized” Xi with sharper megadomains. b Model: In the absence of SMCHD1, Xist-rich chromatin co-segregates, likely via PRC1 self-association, leading to the formation of S1/S2 compartments. The self-association between S1 chromatin creates long-range interaction across the Dxz4 boundary, thus partially obscuring megadomains. c Three major folding mechanisms that define the large-scale Xi architecture: self-association between Xist/H2AK119ub-enriched chromatin to form S1/S2 compartments through PRC1, potential chromatin mixing activity of SMCHD1, and inter-megadomain insulation by Dxz4. When superimposed on the Xi, these folding mechanisms sometimes interfere with each other—SMCHD1 attenuates S1/S2 structure, and PRC1 obscures megadomains