Dataset Information

Structural organization of the inactive X chromosome in the mouse.

ABSTRACT: X-chromosome inactivation (XCI) involves major reorganization of the X chromosome as it becomes silent and heterochromatic. During female mammalian development, XCI is triggered by upregulation of the non-coding Xist RNA from one of the two X chromosomes. Xist coats the chromosome in cis and induces silencing of almost all genes via its A-repeat region, although some genes (constitutive escapees) avoid silencing in most cell types, and others (facultative escapees) escape XCI only in specific contexts. A role for Xist in organizing the inactive X (Xi) chromosome has been proposed. Recent chromosome conformation capture approaches have revealed global loss of local structure on the Xi chromosome and formation of large mega-domains, separated by a region containing the DXZ4 macrosatellite. However, the molecular architecture of the Xi chromosome, in both the silent and expressed regions,remains unclear. Here we investigate the structure, chromatin accessibility and expression status of the mouse Xi chromosome in highly polymorphic clonal neural progenitors (NPCs) and embryonic stem cells. We demonstrate a crucial role for Xist and the DXZ4-containing boundary in shaping Xi chromosome structure using allele-specific genome-wide chromosome conformation capture (Hi-C) analysis, an assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq) and RNA sequencing. Deletion of the boundary disrupts mega-domain formation, and induction of Xist RNA initiates formation of the boundary and the loss of DNA accessibility. We also show that in NPCs, the Xi chromosome lacks active/inactive compartments and topologically associating domains (TADs), except around genes that escape XCI. Escapee gene clusters display TAD-like structures and retain DNA accessibility at promoter-proximal and CTCF-binding sites. Furthermore, altered patterns of facultative escape genes indifferent neural progenitor clones are associated with the presence of different TAD-like structures after XCI. These findings suggest a key role for transcription and CTCF in the formation of TADs in the context of the Xi chromosome in neural progenitors.

SUBMITTER: Giorgetti L

PROVIDER: S-EPMC5443622 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structural organization of the inactive X chromosome in the mouse.

Giorgetti Luca L Lajoie Bryan R BR Carter Ava C AC Attia Mikael M Zhan Ye Y Xu Jin J Chen Chong Jian CJ Kaplan Noam N Chang Howard Y HY Heard Edith E Dekker Job J

Nature 20160718 7613

X-chromosome inactivation (XCI) involves major reorganization of the X chromosome as it becomes silent and heterochromatic. During female mammalian development, XCI is triggered by upregulation of the non-coding Xist RNA from one of the two X chromosomes. Xist coats the chromosome in cis and induces silencing of almost all genes via its A-repeat region, although some genes (constitutive escapees) avoid silencing in most cell types, and others (facultative escapees) escape XCI only in specific co ...[more]

PMID: 27437574

Similar Datasets

Project description:A subset of genomic regions, including one of the female X chromosomes and all imprinted genes, are expressed exclusively from a single allele in somatic cells of mammals. To evaluate structural changes associated with allelic silencing, we used mouse F1 hybrid systems in which X inactivation is skewed and alleles can be distinguished based on single nucleotide polymorphisms to analyze chromatin contacts by a new Hi-C assay that uses DNase I for chromatin fragmentation. Both DNase Hi-C and in situ DNase Hi-C reveal a radically different conformation between the two female mouse X chromosomes. Two superdomains of frequent intrachromosomal contacts separated by a hinge region are specifically observed on the inactive X chromosome both in vivo (brain) and in vitro (Patski cells). A bipartite 3D organization of the inactive X has been also reported in human lymphoblastoid cells, suggesting that this conserved structure probably plays an important role in maintenance of gene silencing on the inactive X. Interestingly, we found that the genomic content of the superdomains differs between species, but that part of the hinge region is conserved and located near the Dxz4/DXZ4 locus that binds CTCF on the inactive X. In mouse, the hinge region also contains a minisatellite Ds-TR adjacent to a promoter with strong CTCF binding. Both Dxz4 and Ds-TR bind nucleophosmin and are enriched in nucleolus-associated chromatin, suggesting anchoring to the nucleolus. Genes that escape X inactivation do not cluster but are preferentially located near the periphery of the 3D structure. Regions enriched in CTCF or RNA polymerase are also preferentially located on the periphery of the inactive X while LINE1 elements are preferentially on the interior. Genes subject to silencing exhibit fewer detectable intrachromosomal contacts than escape genes. This transcription-coupled pattern is also evident for imprinted genes, in which more chromatin contacts are detected on the expressed allele, suggesting greater constraint on the organization of expressed genomic regions.

Dataset Information

Structural organization of the inactive X chromosome in the mouse.

Publications

Structural organization of the inactive X chromosome in the mouse.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets