Megadomains and superloops form dynamically during X-chromosome inactivation but are dispensable for silencing and escape
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA479812 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7473220_1.fastq.gz | Fastqsanger.gz | |||
| SRR7473220_2.fastq.gz | Fastqsanger.gz | |||
| SRR7473230_1.fastq.gz | Fastqsanger.gz | |||
| SRR7473230_2.fastq.gz | Fastqsanger.gz | |||
| SRR7473240_1.fastq.gz | Fastqsanger.gz |
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Project description:The mammalian inactive X-chromosome (Xi) is structurally distinct from all other chromosomes and serves as a model for higher order chromosome organization. The Xi lacks strong topologically associated domains and is instead organized into megadomains and superloops mediated in part by the noncoding loci, Dxz4 and Firre. Their functional significance is presently unclear, though one study suggests that they permit Xi genes to escape silencing. Here, we find that megadomains do not form before silencing spreads along the Xi. Deletional analysis shows that Dxz4, but not Firre, is required for megadomains. Surprisingly, however, deleting neither Dxz4 nor Firre impacts Xi silencing or gene escape. Nor does it affect Xi nuclear localization, stability, or H3K27 methylation. Furthermore, ectopic integration of Dxz4 and Xist is not sufficient to form megadomains on autosomes, thereby uncoupling megadomain formation from chromosomal silencing. We conclude that Dxz4 and megadomains are dispensable for Xi silencing and escape.
2018-10-31 | GSE116649 | GEO
Project description:The mammalian inactive X-chromosome (Xi) is structurally distinct from all other chromosomes and serves as a model for how the 3D genome is organized. The Xi shows weakened topologically associated domains and is instead organized into megadomains and superloops directed by the noncoding loci, Dxz4 and Firre. Their functional significance is presently unclear, though one study suggests that they permit Xi genes to escape silencing. Here, we find that megadomains do not precede Xist expression or Xi gene silencing. Deleting Dxz4 disrupts the sharp megadomain border, whereas deleting Firre weakens intra-megadomain interactions. However, deleting Dxz4 and/or Firre has no impact on Xi silencing and gene escape. Nor does it affect Xi nuclear localization, stability, or H3K27 methylation. Additionally, ectopic integration of Dxz4 and Xist is not sufficient to form megadomains on autosomes. We conclude that Dxz4 and megadomains are dispensable for Xi silencing and escape from X-inactivation.
| S-EPMC6258728 | biostudies-literature
Project description:The spatial proximity between regulatory elements and their target genes has a profound affect on gene expression. X Chromosome Inactivation (XCI) is an epigenetic process by which an entire chromosome is rendered, for the most part, transcriptionally silent. A few genes are known to escape XCI and the mechanism for this escape remains unclear. Here, using mouse trophectodermal stem cells, we address whether specific chromosomal interactions facilitate escape from XCI by bringing escape-specific regulatory elements in close proximity to gene promoters. Our results suggest a model where escape from XCI occurs within topologically associated domains. As such, escaping genes and the regulatory sequences required for their escape are likely located within close linear proximity to each other. The datasets provided include those generated from allele-specific 4C-Seq of genes escaping XCI, genes subject to XCI, and non-genic regions of the X chromosome. FASTQ files, text files containing genomic coordiantes, and BED aligmnets are provided. All sequences were mapped relative to mouse genome build mm9. Deep sequencing of circular chromosome conformation capture (4C-Seq) of genes escaping X inactivation in mouse trophoblast stem cells
2014-03-26 | E-GEOD-49111 | biostudies-arrayexpress
Project description:X chromosome inactivation (XCI) silences most genes on one X chromosome in female mammals, but some genes escape XCI. To identify escape gene in vivo and to explore molecular mechanisms that regulate this process we analyzed the allele-specific expression and chromatin structure of X-linked genes in mouse tissues and cells with skewed XCI and distinguishable alleles based on single nucleotide polymorphisms. Using a new method to estimate allelic expression, we demonstrate a continuum between complete silencing and significant expression from the inactive X (Xi). Few genes (2-3%) escape XCI to a significant level and only a minority differs between mouse tissues, suggesting stringent silencing and escape controls. Allelic profiles of DNase I hypersensitivity and RNA polymerase II occupancy of genes on the Xi correlate with escape from XCI. Allelic binding profiles of the DNA binding protein CCCTC-binding factor (CTCF) in different cell types indicate that CTCF binding at the promoter correlates with escape. Importantly, CTCF binding at the boundary between escape and silenced domains may prevent the spreading of active escape chromatin into silenced domains. Examination of allelic expression in mouse hybrid tissues.
2015-02-20 | E-GEOD-59777 | biostudies-arrayexpress
Project description:X chromosome inactivation (XCI) silences most genes on one X chromosome in female mammals, but some genes escape XCI. To identify escape gene in vivo and to explore molecular mechanisms that regulate this process we analyzed the allele-specific expression and chromatin structure of X-linked genes in mouse tissues and cells with skewed XCI and distinguishable alleles based on single nucleotide polymorphisms. Using a new method to estimate allelic expression, we demonstrate a continuum between complete silencing and significant expression from the inactive X (Xi). Few genes (2-3%) escape XCI to a significant level and only a minority differs between mouse tissues, suggesting stringent silencing and escape controls. Allelic profiles of DNase I hypersensitivity and RNA polymerase II occupancy of genes on the Xi correlate with escape from XCI. Allelic binding profiles of the DNA binding protein CCCTC-binding factor (CTCF) in different cell types indicate that CTCF binding at the promoter correlates with escape. Importantly, CTCF binding at the boundary between escape and silenced domains may prevent the spreading of active escape chromatin into silenced domains. Examination of CTCF and RNA PolIIS5p occupancy in mouse hybrid cells and adult tissues.
2015-02-20 | E-GEOD-59778 | biostudies-arrayexpress
Project description:X chromosome inactivation (XCI) silences most genes on one X chromosome in female mammals, but some genes escape XCI. To identify escape gene in vivo and to explore molecular mechanisms that regulate this process we analyzed the allele-specific expression and chromatin structure of X-linked genes in mouse tissues and cells with skewed XCI and distinguishable alleles based on single nucleotide polymorphisms. Using a new method to estimate allelic expression, we demonstrate a continuum between complete silencing and significant expression from the inactive X (Xi). Few genes (2-3%) escape XCI to a significant level and only a minority differs between mouse tissues, suggesting stringent silencing and escape controls. Allelic profiles of DNase I hypersensitivity and RNA polymerase II occupancy of genes on the Xi correlate with escape from XCI. Allelic binding profiles of the DNA binding protein CCCTC-binding factor (CTCF) in different cell types indicate that CTCF binding at the promoter correlates with escape. Importantly, CTCF binding at the boundary between escape and silenced domains may prevent the spreading of active escape chromatin into silenced domains.
2015-02-20 | GSE59777 | GEO
Project description:The spatial proximity between regulatory elements and their target genes has a profound affect on gene expression. X Chromosome Inactivation (XCI) is an epigenetic process by which an entire chromosome is rendered, for the most part, transcriptionally silent. A few genes are known to escape XCI and the mechanism for this escape remains unclear. Here, using mouse trophectodermal stem cells, we address whether specific chromosomal interactions facilitate escape from XCI by bringing escape-specific regulatory elements in close proximity to gene promoters. Our results suggest a model where escape from XCI occurs within topologically associated domains. As such, escaping genes and the regulatory sequences required for their escape are likely located within close linear proximity to each other. The datasets provided include those generated from allele-specific 4C-Seq of genes escaping XCI, genes subject to XCI, and non-genic regions of the X chromosome. FASTQ files, text files containing genomic coordiantes, and BED aligmnets are provided. All sequences were mapped relative to mouse genome build mm9.
2014-03-26 | GSE49111 | GEO
Project description:Although the chromatin regulator CTCF is enriched at genes escaping from X-chromosome inactivation (XCI), molecular mechanisms remain elusive. We examined CTCF and epigenetic features at escape genes on the inactive X (Xi) in mouse F1 hybrid cells and tissues. We found that escape genes are located inside topologically insulated domains limited by convergent arrays of CTCF binding sites, suggesting loop formation. Xi-specific deletion of a CTCF right boundary of the escape gene Car5b caused loss of CTCF binding and changes of histone modifications at Car5b and abolished escape, suggesting loss of insulation. This is consistent with Car5b lack of escape in mouse brain showing no CTCF binding at the boundary. Inversion of this boundary had no effect on Car5b escape, suggesting that tandem coiled looping could still function as insulation. To test whether chromatin features of the Xi could affect escape we examined mutants in which the Xi-specific compact structure is disrupted or there is loss of H3K27me3 enrichment. We found that both conditions cause an Xi-specific increase in active marks and gene expression at escape regions, suggesting that the 3D structure and heterochromatic marks of the Xi play a role in modulating escape levels of genes insulated by CTCF.
2023-05-18 | GSE231626 | GEO
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