PRC1 collaborates with SMCHD1 to fold the X-chromosome and spread Xist RNA between chromosome compartments

• Published in: Nature communications 2019-07, Vol.10 (1), p.2950-18, Article 2950
• Main Authors: Wang, Chen-Yu, Colognori, David, Sunwoo, Hongjae, Wang, Danni, Lee, Jeannie T.
• Format: Article
• Language: English
• Subjects: 38; 38/32; 38/71; 45; 45/15; 45/23; 45/41; 45/70; 45/91; 631/114/2785; 631/208/176/1433; 631/337/103; Ablation; Activation; Animals; Chromosomal Proteins, Non-Histone - metabolism; Chromosomes; Chromosomes, Mammalian - genetics; Compartments; Deactivation; Deoxyribonucleic acid; Depletion; DNA; DNA methylation; DNA Methylation - genetics; Histones - metabolism; Humanities and Social Sciences; Inactivation; Lysine - metabolism; Mice; Models, Genetic; multidisciplinary; Partitions; Polycomb group proteins; Polycomb Repressive Complex 1 - metabolism; Ribonucleic acid; RNA; RNA, Long Noncoding - metabolism; Science; Science (multidisciplinary); Self-association; Spreading; X Chromosome - chemistry; X Chromosome - genetics; X Chromosome Inactivation - genetics; X chromosomes; X-chromosome inactivation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10755-3

X-chromosome inactivation triggers fusion of A/B compartments to inactive X (Xi)-specific structures known as S1 and S2 compartments. SMCHD1 then merges S1/S2s to form the Xi super-structure. Here, we ask how S1/S2 compartments form and reveal that Xist RNA drives their formation via recruitment of Polycomb repressive complex 1 (PRC1). Ablating Smchd1 in post-XCI cells unveils S1/S2 structures. Loss of SMCHD1 leads to trapping Xist in the S1 compartment, impairing RNA spreading into S2. On the other hand, depleting Xist, PRC1, or HNRNPK precludes re-emergence of S1/S2 structures, and loss of S1/S2 compartments paradoxically strengthens the partition between Xi megadomains. Finally, Xi-reactivation in post-XCI cells can be enhanced by depleting both SMCHD1 and DNA methylation. We conclude that Xist, PRC1, and SMCHD1 collaborate in an obligatory, sequential manner to partition, fuse, and direct self-association of Xi compartments required for proper spreading of Xist RNA. The inactive X (Xi)-specific S1/S2 chromosome compartments are merged by SMCHD1, but how the S1/S2 structure is constructed is unclear. The authors find that PRC1 drives the formation of S1/S2s and that the stepwise folding process of the Xi facilitates Xist RNA spreading between Xi compartments.