Bipartite structure of the inactive mouse X chromosome

Abstract

BackgroundIn mammals, one of the female X chromosomes and all imprinted genes are expressed exclusively from a single allele in somatic cells. To evaluate structural changes associated with allelic silencing, we have applied a recently developed Hi-C assay that uses DNase I for chromatin fragmentation to mouse F1 hybrid systems.ResultsWe find radically different conformations for the two female mouse X chromosomes. The inactive X has two superdomains of frequent intrachromosomal contacts separated by a boundary region. Comparison with the recently reported two-superdomain structure of the human inactive X shows that the genomic content of the superdomains differs between species, but part of the boundary region is conserved and located near the Dxz4/DXZ4 locus. In mouse, the boundary region also contains a minisatellite, Ds-TR, and both Dxz4 and Ds-TR appear to be anchored to the nucleolus. Genes that escape X inactivation do not cluster but are located near the periphery of the 3D structure, as are regions enriched in CTCF or RNA polymerase. Fewer short-range intrachromosomal contacts are detected for the inactive alleles of genes subject to X inactivation compared with the active alleles and with genes that escape X inactivation. This pattern is also evident for imprinted genes, in which more chromatin contacts are detected for the expressed allele.ConclusionsBy applying a novel Hi-C method to map allelic chromatin contacts, we discover a specific bipartite organization of the mouse inactive X chromosome that probably plays an important role in maintenance of gene silencing.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0728-8) contains supplementary material, which is available to authorized users.

Deletion of DXZ4 on the human inactive X chromosome alters higher-order genome architecture

“…Notably, despite extensive rearrangement of the murine X chromosome relative to its human counterpart, the boundary between the superdomains again occurred at Dxz4 [chrX: 75.7-75.8 megabases (Mb), mm10] (18). [While this manuscript was in preparation, this point was reported by multiple groups (19,20).] As in human, we also observed superloops between Dxz4 and Firre, between Dxz4 and Xist, and between Dxz4 and x75 ( Fig.…”

“…A map of the Patski cell line from ref. 19 confirms the lack of compartmentalization on the Xi chromosome in Patski cells. Similarly, in maps of murine fibroblasts (20), the compartment structure on the Xi chromosome was either attenuated or absent.…”

“…Compartment structure was almost entirely absent in the murine Xi chromosome: The Hi-C map of the Xi chromosome did not have a plaid appearance, and square domains were rarely seen along its diagonal. To check whether the absence of compartment structure is a feature of mice in general or of the Patski cell line in particular, we reanalyzed data from the two recent Hi-C studies of murine X chromosome inactivation mentioned above (19,20). A map of the Patski cell line from ref.…”

“…Similarly, in maps of murine fibroblasts (20), the compartment structure on the Xi chromosome was either attenuated or absent. However, maps of murine brain cells (19) exhibited clear compartmentalization on the Xi chromosome (SI Appendix, Fig. S12).…”

Spatial Organization of Chromatin Domains and Compartments in Single Chromosomes

“…Consistent with previous allele-specific Hi-C analyses (21,35,37), Xi was largely partitioned into two contiguous compartments (also called superdomains or megadomains) separated on the genomic map by the DXZ4 macrosatellite (Fig. 4C and fig.…”