X Chromosome Dosage Modulates Multiple Molecular and Cellular Properties of Mouse Pluripotent Stem Cells Independently of Global DNA Methylation Levels
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ABSTRACT:
PROVIDER: PRJNA433190 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6677410.fastq.gz | Fastqsanger.gz | |||
| SRR6677420.fastq.gz | Fastqsanger.gz | |||
| SRR6677411.fastq.gz | Fastqsanger.gz | |||
| SRR6677421.fastq.gz | Fastqsanger.gz | |||
| SRR6677412.fastq.gz | Fastqsanger.gz |
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Project description:During early mammalian development, the two X-chromosomes in female cells are active. Dosage compensation between XX female and XY male cells is then achieved by X-chromosome inactivation in female cells. Reprogramming female mouse somatic cells into induced pluripotent stem cells (iPSCs) leads to X-chromosome reactivation. The extent to which increased X-chromosome dosage (X-dosage) in female iPSCs leads to differences in the molecular and cellular properties of XX and XY iPSCs is still unclear. We show that chromatin accessibility in mouse iPSCs is modulated by X-dosage. Specific sets of transcriptional regulator motifs are enriched in chromatin with increased accessibility in XX or XY iPSCs. We show that the transcriptome, growth and pluripotency exit are also modulated by X-dosage in iPSCs. To understand the mechanisms by which increased X-dosage modulates the molecular and cellular properties of mouse pluripotent stem cells, we used heterozygous deletions of the X-linked gene Dusp9 in XX embryonic stem cells. We show that X-dosage regulates the transcriptome, open chromatin landscape, growth and pluripotency exit largely independently of global DNA methylation. Our results uncover new insights into X-dosage in pluripotent stem cells, providing principles of how gene dosage modulates the epigenetic and genetic mechanisms regulating cell identity.
2018-03-31 | GSE110215 | GEO
Project description:Reprogramming female mouse somatic cells into induced pluripotent stem cells (iPSCs) leads to X-chromosome reactivation. The extent to which increased X-chromosome dosage (X-dosage) in female iPSCs compared with male iPSCs leads to differences in the properties of iPSCs is still unclear. We show that chromatin accessibility in mouse iPSCs is modulated by X-dosage. Specific sets of transcriptional regulator motifs are enriched in chromatin with increased accessibility in XX or XY iPSCs. The transcriptome, growth and pluripotency exit are also modulated by X-dosage in iPSCs. To understand how increased X-dosage modulates the properties of mouse pluripotent stem cells, we used heterozygous deletions of the X-linked gene Dusp9. We show that X-dosage regulates the transcriptome, open chromatin landscape, growth, and pluripotency exit largely independently of global DNA methylation. Our results provide insights into how gene dosage modulates the epigenetic and genetic mechanisms that regulate cell identity.
| S-EPMC6372905 | biostudies-literature
Project description:<p>Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy. </p>
2024-05-23 | MTBLS9677 | MetaboLights
Project description:Studying X-chromosome dosage compensation dynamics in human early embryos using single cell RNA sequencing
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Project description:Drosophila dosage compensation is an epigenetic phenomenon in which the transcription of most genes on X-chromosome is enhanced by approximately two folds in males to equalize that in females. In this study, we provide evidence that transcriptional repressors, such as HP1 and linker histone H1, are globally reduced on male X chromosome. We further investigated the role of HP1 and linker H1 on X chromosome dosage compensation using flies with overexpression of HP1 and H1, we demonstrate that these repressors surpress H4K16 acetylation, presence of the elongating RNA Pol II and the transcription of the genes on male X chromosomes. To understand how H1 and HP1 are regulated on male X chromosome, we next explored the relationship between MOF and the two repressors of chromatin. We show that the hyperacetylation of H4K16 induced by MOF resulted in the loss of H1 and HP1 on chromatin and global chromatin decondensation. Our biochemical analysis further shows that the presence of acetylation on histone H4 at lysine 16 directly inhibits the interaction between histone H4 and linker H1. This study therefore provides novel clues on understanding the dynamic regulation of chromatin regulators on male X chromosome dosage compensation.
2017-11-01 | GSE29537 | GEO
Project description:The Anopheles mosquito is one of thousands of species in which sex differences play a central role in their biology, as only females need a blood meal in order to produce eggs. Sex differentiation is regulated by sex chromosomes, but their presence creates a dosage imbalance between males (XY) and females (XX). Dosage compensation (DC) can re-equilibrate the expression of sex-chromosomal genes, but because the molecular mechanisms providing DC have only been studied in a few model organisms, key questions about its evolutionary diversity and functional necessity remain unresolved. Here, we reveal the DC pathway in the malaria mosquito Anopheles gambiae. We identified SOA, a previously uncharacterized gene, whose expression is sufficient to induce a global upregulation of X-linked genes. Sex-specific alternative splicing prevents the production of a functional SOA protein in females. The male SOA isoform encodes a DNA-binding protein that recognizes the promoters of X chromosomal genes through a CA repeat sequence. Male mosquitos lacking SOA exhibit a chromosome-wide downregulation of the X, which is compatible with viability, but causes a developmental delay. Thus, our molecular analysis of the first DC master regulator in a non-model organism elucidates the evolutionary steps leading to the establishment of a chromosome-specific fine-tuning mechanism.
2023-07-13 | PXD042353 | Pride
Project description:Cohesin, a chromatin-associated protein complex with four core subunits (Smc1a, Smc3, Rad21 and either Stag1 or 2), has a central role in cell proliferation and gene expression in metazoans. Human developmental disorders termed “cohesinopathies” are characterised by germline mutations in cohesin or its regulators that do not entirely eliminate cohesin function. However, it is not clear if mutations in individual cohesin subunits have independent developmental consequences. Using zebrafish rad21 or stag2 mutants to change cohesin complex quantity or composition, we show that these parameters independently influence embryonic tailbud development. Both mutants have altered mesoderm induction, but only homozygous or heterozygous rad21 mutation affects cell cycle gene expression. stag2 mutants have slimmer notochords and reduced Wnt signaling in neuromesodermal progenitors as revealed by single cell RNA-sequencing. Stimulation of Wnt signaling rescues transcription and morphology in stag2, but not rad21 mutants, implying that individual cohesin mutations respond independently to cell signaling. Our results have implications for the understanding and management of cohesinopathies.
2023-11-29 | GSE247246 | GEO
Project description:Cohesin, a chromatin-associated protein complex with four core subunits (Smc1a, Smc3, Rad21 and either Stag1 or 2), has a central role in cell proliferation and gene expression in metazoans. Human developmental disorders termed “cohesinopathies” are characterised by germline mutations in cohesin or its regulators that do not entirely eliminate cohesin function. However, it is not clear if mutations in individual cohesin subunits have independent developmental consequences. Using zebrafish rad21 or stag2 mutants to change cohesin complex quantity or composition, we show that these parameters independently influence embryonic tailbud development. Both mutants have altered mesoderm induction, but only homozygous or heterozygous rad21 mutation affects cell cycle gene expression. stag2 mutants have slimmer notochords and reduced Wnt signaling in neuromesodermal progenitors as revealed by single cell RNA-sequencing. Stimulation of Wnt signaling rescues transcription and morphology in stag2, but not rad21 mutants, implying that individual cohesin mutations respond independently to cell signaling. Our results have implications for the understanding and management of cohesinopathies.
2023-11-29 | GSE248952 | GEO
Project description:Aneuploidy, an imbalance in chromosome copy numbers, causes genetic disorders, and drives cancer progression, drug tolerance, and antimicrobial resistance. While aneuploidy can confer stress resistance, it is not well understood how cells overcome the fitness burden caused by aberrant chromosomal copy numbers. Studies using both systematically generated and natural aneuploid yeasts triggered an intense debate about the role of dosage compensation, concluding that aneuploidy is transmitted to the transcriptome and proteome without significant buffering at the chromosome-wide level, and is, at least in lab strains, associated with significant fitness costs. Conversely, systematic sequencing and phenotyping of large collections of natural isolates revealed that aneuploidy is frequent and has few, if any, fitness costs in nature. To address these discrepant findings, we developed a platform that yields highly precise proteomic measurements across large numbers of genetically diverse samples and applied it to natural isolates collected as part of the 1011 genomes project (Peter, J. et al, 2018). For 613 of the isolates, we were able to match the proteomes to their corresponding transcriptomes and genomes, subsequently quantifying the effect of aneuploidy on gene expression by comparing 95 aneuploid with 518 euploid strains. We find, as in previous studies, that aneuploid gene dosage is not buffered chromosome-wide at the transcriptome level. Importantly, in the proteome, we detect an attenuation of aneuploidy by about 25% below the aneuploid gene dosage in natural yeast isolates. Furthermore, this chromosome-wide dosage compensation is associated with the ubiquitin-proteasome system (UPS), which is expressed at higher levels and has increased activity across natural aneuploid strains. Thus, through systematic exploration of the species-wide diversity of the yeast proteome, we shed light on a long-standing debate about the biology of aneuploids, revealing that aneuploidy tolerance is mediated through chromosome-wide dosage compensation at the proteome level.
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Project description:We have conducted a global analysis of somatic dosage compensation and also asked if germ cell dosage compensate by microarray analysis of gene expression in wild-type tissues. To obviate the confounding effects of scatter and especially the skewed genomic distributions of genes with sex-biased expression in both the soma and germline [there are fewer X chromosome genes with male-biased expression], we used mutations that transform sexual identity. In the soma we used gain-of-function transformer to turn X;AA flies into somatic females with tumorous germlines. The gonadectomized somas of these X;AA female flies were compared to similarly prepared XX;AA females. The X;AA ovarian tumors, which are possibly the result of germline sex transformations, were compared to the similar XX;AA ovarian tumors generated with loss-of-function alleles of ovarian tumor and Sex-lethal. We used alleles of transformer-2 and doublesex to transform XX;AA flies into somatic males with atrophic germlines. Keywords: other
2005-12-15 | GSE2119 | GEO