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DNA methylation profiling in X;autosome translocations supports a role for L1 repeats in the spread of X chromosome inactivation

ABSTRACT: In order to test the hypothesis that X chromosome inactivation shows sequence specificity, we have analysed the spread of XCI into autosomal chromatin by performing DNA methylation profiling in six unbalanced X;autosome translocations. Using promoter hypermethylation as an epigenetic signature of XCI, we have determined the inactivation status of 1,050 autosomal genes after translocation onto the inactive X. By performing a comparative sequence analysis of autosomal genes that are either subject to or escape the X inactivation signal, we identified a number of common repetitive elements, including LINEs, and DNA motifs that are significantly enriched around inactive autosomal genes. We show that these same motifs predominantly map to L1P elements, are significantly enriched on the X chromosome versus the autosomes, and also occur at higher densities around X-linked genes that are subject to X inactivation compared to those that escape X inactivation. These results are consistent with a potential causal relationship between DNA sequence features such as L1s and the spread of XCI, lending strong support to Mary Lyon's 'repeat hypothesis'.

ORGANISM(S): Homo sapiens

PROVIDER: GSE50837 | GEO | 2013/09/13

SECONDARY ACCESSION(S): PRJNA219131

REPOSITORIES: GEO

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DNA methylation profiling in X;autosome translocations supports a role for L1 repeats in the spread of X chromosome inactivation

Project description:In order to test the hypothesis that X chromosome inactivation shows sequence specificity, we have analysed the spread of XCI into autosomal chromatin by performing DNA methylation profiling in six unbalanced X;autosome translocations. Using promoter hypermethylation as an epigenetic signature of XCI, we have determined the inactivation status of 1,050 autosomal genes after translocation onto the inactive X. By performing a comparative sequence analysis of autosomal genes that are either subject to or escape the X inactivation signal, we identified a number of common repetitive elements, including LINEs, and DNA motifs that are significantly enriched around inactive autosomal genes. We show that these same motifs predominantly map to L1P elements, are significantly enriched on the X chromosome versus the autosomes, and also occur at higher densities around X-linked genes that are subject to X inactivation compared to those that escape X inactivation. These results are consistent with a potential causal relationship between DNA sequence features such as L1s and the spread of XCI, lending strong support to Mary Lyon's 'repeat hypothesis'. Genome-wide measurement of CpG methylation levels by hybridizing bisulphite-converted DNA to Infinium HumanMethylation450 BeadChips. Eight DNA samples extracted from individuals carrying X;autosome translocations were processed according to manufacturer's recommended protocols, and array data processed using the Methylation Module of GenomeStudio v1.8 software with default parameters.

2013-09-13 | E-GEOD-50837 | biostudies-arrayexpress

Structural organization of the inactive X chromosome

Project description:X-chromosome inactivation (XCI) entails a massive structural reorganization of the inactive X (Xi). However the molecular architecture of the Xi is unknown. Here we show that the Xi lacks typical autosomal features such as active/inactive compartments and topologically associating domains (TADs), except around a small number of genes that escape XCI and remain expressed. Escaping genes form TADs and retain DNA accessibility at promoter-proximal and CTCF binding sites, indicating that these loci can avoid Xist-mediated erasure of chromosomal structure. We further show that genesilencing competent Xist RNA is sufficient to induce segregation of the Xi into two ‘mega-domains’ separated by a boundary that includes the DXZ4 macrosatellite. Deletion of this boundary prior to XCI results in fusion of the megadomains and altered patterns of escape that correlate with changes in TAD structure following differentiation and XCI . Our results suggest a critical role for the boundary locus and Xist RNA in shaping the structure of the Xi and modulating escape from XCI. Our findings also point to roles of transcription and CTCF binding in TAD formation in the context of facultative heterochromatin.

2016-07-18 | GSE72697 | GEO

Escape from X chromosome inactivation occurs within topologically associated domains

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

Escape from X inactivation in mouse tissues (RNA-Seq)

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

Escape from X inactivation in mouse tissues (ChIP-Seq)

2015-02-20 | E-GEOD-59778 | biostudies-arrayexpress

Escape from X chromosome inactivation occurs within topologically associated domains

2014-03-26 | GSE49111 | GEO

The efficiency of Xist-mediated silencing of X-linked and autosomal genes is determined by the genomic environment

Project description:Xist is indispensable for X chromosome inactivation (XCI) in female mammalian cells. However, how Xist RNA directs chromosome-wide transcriptional inactivation of the X chromosome is largely unknown. Here, to study chromosome inactivation by Xist, we generated a system where ectopic Xist expression can be induced from several genomic contexts in aneuploid mouse ES cells. We found that ectopic Xist expression from any location on the X chromosome faithfully recapitulated endogenous XCI, showing the potency of Xist to initiate XCI. Genes that escape XCI remain consistently transcriptionally active upon ectopic XCI, regardless of their position relative to Xist transgenes, and the enrichment of CTCF at their promoters is implicated in directing XCI escape. Xist expression from autosomes facilitates their transcriptional silencing to different degrees, and gene density in proximity of the Xist transcription locus plays a central role in determining the efficiency of gene inactivation. We also show that the enrichment of LINE elements together with a specific chromatin environment facilitates Xist-mediated silencing of both X-linked and autosomal genes. These findings provide new insights into the epigenetic mechanisms that mediate XCI and identify genomic features that promote Xist-mediated chromosome-wide gene inactivation

2017-07-04 | GSE92894 | GEO

Regulation of mouse X inactivation (ChIP-Seq)

2015-02-20 | GSE59778 | GEO

Escape from X inactivation in mouse tissues (RNA-Seq)

2015-02-20 | GSE59777 | GEO

Landscape of DNA methylation on the X chromosome reflects CpG density, functional chromatin state and X-chromosome inactivation.

Project description:X-chromosome inactivation (XCI) achieves dosage compensation between males and females through the silencing of the majority of genes on one X chromosome, with approximately 15% of genes reported to show inactive X (Xi) expression. We examined the interplay between ChromHMM states, CpG density, expression and DNAm from over 1800 female samples with the Illumina 450K array. The interaction between CpG density and histone marks differed between the active X (Xa) and the Xi, with X-linked promoters reflecting transcriptional status, while the Xi showed lower DNAm than the Xa at all non-promoter regions. Promoter DNAm was used to determine a novel XCI status for more than 100 transcription start sites and a comparison across 27 tissues revealed the majority of genes were consistently subject to XCI. Inter-female and twin data supported a model of predominately cis-acting influences on escape, or variable escape, from XCI. Increased promoter DNAm at escape genes correlated with decreased relative Xi expression up to ~15% female DNAm but above this threshold DNAm was not correlated with the stability of silencing. Xi DNAm was ~12% lower than Xa DNAm within the gene bodies of subject genes and between genes while there was equivalent DNAm at escape genes. In addition to offering insight into sex-specific difference in disease, female X chromosomes provide the opportunity to compare euchromatin and heterochromatin of allelic regions within the same nuclear environment and demonstrate the correlation of DNAm with transcription and the influences of CpG density and chromatin marks.

2014-11-29 | GSE60275 | GEO

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