Bipartite structure of the inactive mouse X chromosome

Xinxian Deng, Wenxiu Ma, Vijay Ramani, Andrew Hill, Fan Yang, Ferhat Ay, Joel B. Berletch, Carl Anthony Blau, Jay Shendure, Zhijun Duan, William S. Noble, Christine M. Disteche

In 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. We find radically different conformations for the two female mouse X chromosomes. The inactive X has two superdomains of frequent intrachromosomal contacts separated by a hinge region. Comparison with the recently reported bipartite 3D structure of the human inactive X shows that the genomic content of the superdomains differs between species, but part of the hinge is conserved and located near the Dxz4/DXZ4 locus. In mouse, the hinge 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 to the active alleles and to genes that escape X inactivation. This pattern is also evident for imprinted genes, in which more chromatin contacts are detected for the expressed allele. By 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.