Chromosome X Mosaicism Methylation Study
Ontology highlight
ABSTRACT: This study investigates methylation patterns in promoter regions on the X chromosomes of females with X chromosome mosaicism in an effort to phase mosaic events to either the active or inactive X chromosome.
SECONDARY ACCESSION(S): PRJNA320447PRJNA320448
REPOSITORIES: dbGaP
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Project description:X chromosome inactivation (XCI) is a dosage compensation mechanism that silences the majority of genes on one X chromosome in each female cell. In order to characterize epigenetic changes that accompany this process, we measured DNA methylation levels in both 45,X Turner syndrome patients, who carry a single active X chromosome (Xa) and normal 46,XX females, who carry one Xa and one inactive X (Xi). Methylated DNA was immunoprecipitated and hybridized to tiling oligonucleotide arrays, generating epigenetic profiles of active and inactive X chromosomes. We observed that XCI is accompanied by changes in DNA methylation specifically at CpG islands. While the majority of CpG islands show increased methylation levels on the Xi, XCI results in reduced methylation at ~20% of CpG islands. Both intra- and inter-genic CpG islands are epigenetically modified, with the biggest increase in methylation occuring at the promoters of genes silenced by XCI. In contrast, genes escaping XCI have low levels of promoter methylation, while genes that undergo polymorphic silencing show intermediate increases in methylation proportionate to their frequency of inactivation. Thus promoter methylation and susceptibility to XCI are correlated. We observed a global correlation between CpG island methylation and the evolutionary age of different X chromosome strata, and that genes escaping XCI show increased methylation within gene bodies. We utilized our epigenetic map to predict both novel genes escaping XCI, and to identify sequence features that may contribute to the XCI process. Finally, as our study included Turner syndrome patients with single X chromosomes of both maternal and paternal origin we searched for parent-of-origin specific methylation differences, but found no evidence to support imprinting on the human X chromosome. Our study provides the first epigenetic profile of active and inactive X chromosomes, giving novel insights into the phenomenon of dosage compensation. Methylated DNA was enriched by immunoprecipitation using antibodies against 5-methylcytosine. meDIP and input DNA was labeled with cy5 and cy3 respectively and hybridized to Nimblegen arrays comprising 2.1 million 50-85mers covering human chromosomes 20, 21, 22, X and Y at a mean density of ~1 probe per 100bp. Resulting log2 fluorescence ratios correspond to methylation levels. Seven patients with Turner syndrome (45,X karyotype), and three normal females (46,XX karyotype) were analyzed. Of the Turner syndrome cases, four had a maternally-derived X, and three had a paternally-derived X chromosome.
2010-07-20 | E-GEOD-22551 | biostudies-arrayexpress
Project description:X chromosome inactivation (XCI) is a dosage compensation mechanism that silences the majority of genes on one X chromosome in each female cell. In order to characterize epigenetic changes that accompany this process, we measured DNA methylation levels in both 45,X Turner syndrome patients, who carry a single active X chromosome (Xa) and normal 46,XX females, who carry one Xa and one inactive X (Xi). Methylated DNA was immunoprecipitated and hybridized to tiling oligonucleotide arrays, generating epigenetic profiles of active and inactive X chromosomes. We observed that XCI is accompanied by changes in DNA methylation specifically at CpG islands. While the majority of CpG islands show increased methylation levels on the Xi, XCI results in reduced methylation at ~20% of CpG islands. Both intra- and inter-genic CpG islands are epigenetically modified, with the biggest increase in methylation occuring at the promoters of genes silenced by XCI. In contrast, genes escaping XCI have low levels of promoter methylation, while genes that undergo polymorphic silencing show intermediate increases in methylation proportionate to their frequency of inactivation. Thus promoter methylation and susceptibility to XCI are correlated. We observed a global correlation between CpG island methylation and the evolutionary age of different X chromosome strata, and that genes escaping XCI show increased methylation within gene bodies. We utilized our epigenetic map to predict both novel genes escaping XCI, and to identify sequence features that may contribute to the XCI process. Finally, as our study included Turner syndrome patients with single X chromosomes of both maternal and paternal origin we searched for parent-of-origin specific methylation differences, but found no evidence to support imprinting on the human X chromosome. Our study provides the first epigenetic profile of active and inactive X chromosomes, giving novel insights into the phenomenon of dosage compensation.
2010-07-20 | GSE22551 | GEO
Project description:Recent studies have shown that repressive chromatin machinery, including DNA methyltransferases (DNMTs) and Polycomb Repressor Complexes (PRCs), bind to chromosomes throughout mitosis and their depletion results in increased chromosome size. Enzymes that catalyse H3K9 methylation, such as Suv39h1, Suv39h2, G9a, GLP are also retained by mitotic chromosomes. Surprisingly however, mutants lacking H3K9me3 have unusually small and compact mitotic chromosomes that are associated with increased H3S10ph and H3K27me3 levels. Chromosome size and centromere compaction in these mutants was rescued by providing exogenous Suv39h1, or inhibiting Ezh2 activity. Quantitative proteomic comparisons of native mitotic chromosomes isolated from wildtype versus Suv39h1,2 double null ESCs revealed that H3K9me3 was essential for the efficient retention of bookmarking factors such as Esrrb. These results highlight an unexpected role for repressive heterochromatin domains in preserving transcription factor binding through mitosis, and underscore the importance of H3K9me3 for sustaining chromosome architecture and epigenetic memory during cell division.
2022-10-12 | PXD030771 | Pride
Project description:Recent studies have shown that repressive chromatin machinery, including DNA methyltransferases and Polycomb Repressor Complexes, bind to chromosomes throughout mitosis and their depletion results in increased chromosome size. Here we show that enzymes that catalyse H3K9 methylation, such as Suv39h1, Suv39h2, G9a and Glp, are also retained on mitotic chromosomes. Surprisingly however, mutants lacking H3K9me3 have unusually small and compact mitotic chromosomes associated with increased H3S10ph and H3K27me3 levels. Chromosome size and centromere compaction in these mutants were rescued by providing exogenous Suv39h1, or inhibiting Ezh2 activity. Quantitative proteomic comparisons of native mitotic chromosomes isolated from wildtype versus Suv39h1/Suv39h2 double-null mouse ESCs revealed that H3K9me3 was essential for the efficient retention of bookmarking factors such as Esrrb. These results highlight an unexpected role for repressive heterochromatin domains in preserving transcription factor binding through mitosis, and underscore the importance of H3K9me3 for sustaining chromosome architecture and epigenetic memory during cell division.
2023-01-25 | PXD039521 | Pride
Project description:In mammals, dosage compensation for the sex chromosomes is achieved by transcriptional silencing of one of the two X chromosomes in females. The inactive X adopts a particular epigenetic state, characterised by specific histones, histone marks, DNA methylation and 3D chromatin structure. As allelic resolution with short-read sequencing is limited, we do not yet have chromosome-wide phased methylomes of the active and inactive X. In this study, we obtained such complete X methylomes in mouse placenta and neural stem cells (NSCs) via long-read nanopore sequencing. This accession corresponds to the RNA-seq for the NSCs.
2024-10-31 | E-MTAB-14486 | biostudies-arrayexpress
Project description:Mammalian chromosomes are folded into intricate hierarchies of interaction domains, within which topologically associating domains (TADs) and CTCF-associated loops partition the physical interactions between regulatory sequences. Current understanding of chromosome folding largely relies on chromosome conformation capture (3C)-based experiments, where chromosomal interactions are detected as ligation products after crosslinking of chromatin. To measure chromosome structure in vivo, quantitatively and without relying on crosslinking and ligation, we have implemented a modified version of damID named damC. DamC combines DNA-methylation based detection of chromosomal interactions with next-generation sequencing and a biophysical model of methylation kinetics. DamC performed in mouse embryonic stem cells provides the first in vivo validation of the existence of TADs and CTCF loops and confirms 3C-based measurements of the scaling of contact probabilities. Combining damC with transposon-mediated genomic engineering shows that new loops can be formed between ectopically introduced and endogenous CTCF sites, which alters the partitioning of physical interactions within TADs. This orthogonal approach to 3C provides the first crosslinking- and ligation-free validation of the existence of key structural features of mammalian chromosomes and provides novel insights into how chromosome structure within TADs can be manipulated.
2019-06-03 | PXD013507 | Pride
Project description:Epigenetic alterations play significant roles in the melanoma tumorigenesis and malignant progression. We profiled genome-wide promoter DNA methylation patterns of melanoma cells deribed from primary lesions of Radial Growrth phase (RGP) and Vertical Growth Phase (VGP), metastatic lesions, and primary normal melanocytes by interrogating 14,495 genes using Illumina bead chip technology. By comparative analysis of the promoter methylation profiles, we identified epigenetically silenced gene signatures that potentially associated with malignant melanoma progression.
2013-12-20 | GSE53516 | GEO
Project description:To compensate for the increased dosage of X chromosomes in females one of the two X chromosomes is inactivated in eutherian mammals in an Xist-dependent manner. Xist is, however, not found in metatherians. Here we describe long non-coding RNA Rsx (RNA-on-the-silent X) that exhibits properties consistent with a role in X-inactivation in opossum. Rsx is abundantly expressed in females but not males and is transcribed from, and coats, the inactive X chromosome copy. Furthermore, when both X chromosomes are active, Rsx is silenced. We used RNA-Seq to determine exon-intron structure and expression level of Rsx in males and females.
2012-06-11 | GSE36861 | GEO
Project description:Stem cells are able to self-renew and also generate differentiated progeny. How gene expression patterns are transmitted through mitosis remains unresolved. Conventional studies have relied upon rigorous cell-cycle-stage synchronisation to find factors in mitotic lysates that could ‘bookmark’ the genome. Here we use an alternative approach, purifying native-unfixed mitotic chromosomes from different cell types using flow cytometry and directly identifying chromosome-bound proteins by LC-MS/MS. This revealed a rich profile of pluripotency- and lineage-specific transcription factors that remained bound to mitotic chromosomes in pluripotent ESCs and lymphocytes, as well as factors implicated in chromosome condensation, architecture and gene silencing. Removal of DNA methylation, PRC2 activity, or in situ cleavage of cohesin, each resulted in the reduced compaction of mitotic chromosomes. These data provide a comprehensive catalogue of bookmarking factors in pluripotent versus lineage-restricted cells and demonstrate an expected duality of function by candidates in regulating both gene expression and mitotic chromosome structure.
2020-06-15 | PXD015251 | Pride
Project description:To compensate for the increased dosage of X chromosomes in females one of the two X chromosomes is inactivated in eutherian mammals in an Xist-dependent manner. Xist is, however, not found in metatherians. Here we describe long non-coding RNA Rsx (RNA-on-the-silent X) that exhibits properties consistent with a role in X-inactivation in opossum. Rsx is abundantly expressed in females but not males and is transcribed from, and coats, the inactive X chromosome copy. Furthermore, when both X chromosomes are active, Rsx is silenced. We used RNA-Seq to determine exon-intron structure and expression level of Rsx in males and females. RNA sequencing was used to detect and characterize transcripts with strongly biased female expression.
2012-06-11 | E-GEOD-36861 | biostudies-arrayexpress