Fig. 7: Escapee distribution on the Xi and the identification of SD–SD interactions in SmcHD1-KO NPC Hi-C data.
From: Replication dynamics identifies the folding principles of the inactive X chromosome
a, Comparison of gene density on the X among RT classes (genes per Mb). Top, mouse annotated genes (mm9 Ref-seq genes); middle, escapees17; bottom, escapees normalized by Ref-seq gene density. b, Densities of all annotated Ref-seq genes and escapees17 normalized by Ref-seq gene density (middle) relative to significant interchromosomal interaction frequency as assayed by virtual 4C of NPCs (bottom)11. c, Similar plots to b were made after virtual 4C (388 viewpoints, 400-kb each) of the human X chromosome using a hTERT-RPE1 Hi-C data18. The inactive (genes subject to stable XCI), variable (genes variably escaping from XCI) and escapee genes were defined based on a systematic human transcriptome study56. Shown are their densities normalized by UCSC gene density. P values in b and c were obtained from Kendall’s rank correlation test with the Bonferroni correction. d, Comparison of Xi probability of X-linked gene expression in SmcHD1-mutant (KO) and WT NPCs as in Fig. 4a,b. Genes were classified into nonescapees and escapees17 and into SD, SI, CL and CE classes. P values were obtained from one-sided paired Wilcoxon signed-rank test. N, the number of X-linked genes in each class. e, Hi-C heatmaps of the mus-Xi in WT and SmcHD1-mutant (KO) NPCs from Wang et al.11 (250-kb resolution). Black circles on Hi-C heatmaps indicate strong SD–SD interactions found in SmcHD1-mutant NPCs. The bottom panel shows enlarged views of blue boxes in the top panel. Magenta, SD domains; blue arrows, Dxz4. f, Aggregated plots of interactions between SD (left) and random bins (right) by Hi-C. g, A proposed model for the formation of the multi-layered 3D structural organization of the Xi. During XCI, an EtoL compartment switch of the Xi occurs first (SD and SI domains) and is followed by a further 3D reorganization of the Xi through the actions of factors such as SmcHD1. Without SmcHD1, the Xi fails to maintain its late replication and 3D structure later during differentiation, resulting in frequent protrusion of SD domains located close to the surface of the Xi (but not SI domains), which occasionally interact with each other. Whereas the figure shows the contact between protruded SD domains, it is also possible that SD–SD domain interactions could occur inside the Xi core (Supplementary Text 2).
