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.
Highlights
In mammals, one of the female X chromosomes and all imprinted genes are expressed exclusively from a single allele in somatic cells
By applying our DNase Hi-C approach [23] as well as the new adapted in situ DNase Hi-C protocol to the mouse F1 hybrid systems described above, we demonstrate that the mouse inactive X chromosome (Xi) condenses in a bipartite structure both in the Patski cell line and in mouse brain, representing the first such analysis in vivo
The inactive mouse X chromosome forms a bipartite structure in cultured cells and tissue We used DNase Hi-C and a modified in situ DNase Hi-C to obtain allele-specific maps of intrachromosomal contacts on the mouse X chromosomes and autosomes
Summary
One of the female X chromosomes and all imprinted genes are expressed exclusively from a single allele in somatic cells. X-linked genes are subject to silencing by X chromosome inactivation (XCI) on one of the two homologs in female somatic cells [2], and a subset of autosomal genes are subject to imprinting and expressed from either the paternal or maternal allele [3]. Imprinted genomic regions undergo epigenetic and conformational changes associated with silencing of one allele [3]. Such conformation changes are considered to involve the formation of loops that bring enhancers and promoters together at the expressed allele [6, 7]
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