Abstract
The mammalian inactive X chromosome (Xi) condenses into a bipartite structure with two superdomains of frequent long-range contacts, separated by a hinge region. Using Hi-C in edited mouse cells with allelic deletions or inversions within the hinge, here we show that the conserved Dxz4 locus is necessary to maintain this bipartite structure. Dxz4 orientation controls the distribution of contacts on the Xi, as shown by a massive reversal in long-range contacts after Dxz4 inversion. Despite an increase in CTCF binding and chromatin accessibility on the Xi in Dxz4-edited cells, only minor changes in TAD structure and gene expression were detected, in accordance with multiple epigenetic mechanisms ensuring X silencing. We propose that Dxz4 represents a structural platform for frequent long-range contacts with multiple loci in a direction dictated by the orientation of its bank of CTCF motifs, which may work as a ratchet to form the distinctive bipartite structure of the condensed Xi.
Highlights
The mammalian inactive X chromosome (Xi) condenses into a bipartite structure with two superdomains of frequent long-range contacts, separated by a hinge region
Similar numbers of allelic reads confirmed the presence of one Xa and one Xi (Supplementary Data 1), which was verified by karyotyping and fluorescence in situ hybridization (FISH) analyses
A deletion of Dxz[4] alone (44 kb), which is much smaller than those previously reported in mouse embryonic stem (ES) cells and in human fibroblasts (200–300 kb), is sufficient to cause de-condensation of the Xi8,9
Summary
The mammalian inactive X chromosome (Xi) condenses into a bipartite structure with two superdomains of frequent long-range contacts, separated by a hinge region. We propose that Dxz[4] represents a structural platform for frequent long-range contacts with multiple loci in a direction dictated by the orientation of its bank of CTCF motifs, which may work as a ratchet to form the distinctive bipartite structure of the condensed Xi. Mammalian X chromosome inactivation (XCI) results in the silencing of one of the two X chromosomes in female somatic cells. In addition to Dxz[4], the mouse hinge region originally defined using Hi-C contains the mouse-specific minisatellite repeat Ds-TR whose function is unknown[7,12] Both Dxz[4] and Ds-TR loci bind nucleophosmin, an essential component of the nucleolus, and could represent a large nucleolusassociated domain that may help position the Xi near the nucleolus[7,15]. We conclude that Dxz[4] alone is necessary for maintenance of the condensed structure of the Xi in mouse fibroblasts, and that the distribution of contacts on the Xi depends on Dxz[4] orientation
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