Modeling sex differences in humans using isogenic induced pluripotent stem cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE145079 | GEO | 2022/11/24
REPOSITORIES: GEO
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Project description:We developed a cellular model to study sex differences in humans. Using somatic cells from a mosaic Kleinefelter patient, we generated isogenic human induced pluripotent stem cell lines with different sex chromosome complements – 47,XXY / 46,XX / 46,XY and 45,X0. 46, XX and 46, XY hiPSCs were differentiated to neural progenitor cells and compared.
2022-11-24 | GSE145118 | GEO
Project description:Klinefelter syndrome (KS) is the most prevalent aneuploidy in males and is characterized by an extra copy of the X chromosome,while the non-mosaic form of KS with 47,XXY karyotype is the most frequent (80-90%), less common non-disjunction events during the early mitotic division of the zygote result in mosaic forms of KS (47,XXY/46,XY). Here, using a paradigmatic cohort of KS-inducible pluripotent stem cells (iPSCs) carrying 47,XXY karyotypes we present the first iPSC-based disease-modeling study performed on KS patients from Saudi Arabia. We profiled the transcriptome of these Saudi KS-iPSCs, virtually characterized by subduedcgenetic backgrounds. Moreover, we performed a comparative transcriptomic analysis to assess the aberrant gene expression profile due to X dosage imbalance in four Saudi and five European and North American 47,XXY patients-derived iPSCs from our previously published study on KS and high-grade sex chromosome aneuploidies (SCAs). We identified a transcriptomic signature including ten PAR1 genes and thirteen non-PAR escape genes consistently upregulated in KS compared to 46,XY controls in both groups, as well as 193 consistenty disregulated autosomal genes. Our results indicate that the global transcriptional impact of X chromosome overdosage in KS is largely attributable to X-linked genes escaping X inactivation, regardless of the geographical area of origin, ethnicity, and genetic background.
2023-08-02 | GSE220268 | GEO
Project description:Analysis of gene expression in the striatum in a mouse model of Klinefelter Syndrome (the Sex Chromosome Trisomy model). The hypothesis tested was that feminization of partner preference was also reflected on a molecular level 4 different genotypes were analyzed (XX female, XY male, XXY male, XX male). There were 8-12 biological replicates per genotype for a total of 38 samples.
2013-07-12 | E-GEOD-48784 | biostudies-arrayexpress
Project description:Detection of genomic rearrangements from a single cell instead of a population of cells is an emerging research technique with important applications in the study of human fertility, constitutional chromosomal disorders, and tumor progression. Here, we develop a method to improve the detection of single-cell genome-wide copy number variation. At this study, 7 amplified single cell DNA samples derived from EBV-line [47,XY,+21], [46,XY,der(20),t(18;20)(p11.21;p13)], [46,XX,del(18)(p11.21->pter)], [46,X,der(X),t(X;14)(q21.1;q12.2)] were analyzed by Agilent 244K array CGH. For these single cell Agilent 244K array CGH analyses: non-amplified genomic DNA extracted from the blood of a Klinefelter patient (XXY) was used as a reference sample. As a validation, the corresponding non-amplified genomic DNA samples were analyzed by 250K Nsp I SNP arrays (platform GPL3718). Non-amplified genomic DNA extracted from the blood of a Klinefelter patient (XXY) was used as a reference sample for BAC array CGH
2011-08-23 | E-GEOD-27892 | biostudies-arrayexpress
Project description:Most autoimmune diseases have a higher incidence in women than men due to differences in sex hormones, sex chromosomes, or both. Female (XX) and male (XY) sex chromosome complements differ in parent-of-origin of the X chromosome, with females inheriting one each from the mother and father, while males inherit only one from the mother2. Here, we discovered that the paternal X (Xp) had higher DNA methylation than the maternal X (Xm) in autoantigen specific CD4+ T lymphocytes, potentially suppressing X gene expression in XX. Using the “Four Core Genotypes” model, the transcriptomes of autoantigen specific CD4+ T lymphocytes showed higher expression of many X genes in XY- than XX. Expression of toll-like receptor 7 (Tlr7) and forkhead box P3 (FoxP3), two X chromosome genes important in autoimmunity, was higher in XY- than XX, confirming genome wide methylation and transcription data. Thus, parent-of-origin differences in DNA methylation of X genes can lead to sexual dimorphisms in gene expression during autoimmunity.
2019-12-11 | GSE122787 | GEO
Project description:Differences in male vs. female immune responses are well-documented and have significant clinical implications. While the immunomodulatory effects of sex hormones are well established, the contributions of sex chromosome complement (XX vs. XY) and gut microbiome diversity on immune sexual dimorphisms have only recently become appreciated. Here we investigate the individual and collaborative influences of sex chromosome complements and gut microbiome bacteria on humoral immune activation. Sham-operated and gonadectomized male and female Four Core Genotype (FCG) mice were immunized with heat-killed Streptococcus pneumoniae (HKSP). Humoral immune responses were assessed and X-linked immune-related gene expression was evaluated to explain the identified XX-dependent phenotypes. Ex vivo studies investigated the functional role of Kdm6a, an X-linked epigenetic regulatory gene of interest, in mitogenic B cell activation. We further evaluated whether gut microbiome communities, or their metabolites, differentially influence immune cell activation in a sex chromosome-dependent manner. Endogenous gut microbiomes were antibiotically depleted and reconstituted with select short-chain fatty acid (SCFA)-producing bacteria prior to HKSP immunization and immune responses assessed. XX mice exhibited higher HKSP-specific IgM-secreting B cells and plasma cell frequencies than XY mice, regardless of gonadal sex. Although Kdm6a was identified as an X-linked gene overexpressed in XX B cells, inhibition of its enzymatic activity did not affect mitogen-induced plasma cell differentiation or antibody production in a sex chromosome-dependent manner ex vivo. Enhanced humoral responses in XX vs. XY immunized FCG mice were eliminated after microbiome depletion, indicating that the microbiome contributes to the identified XX-dependent immune enhancement. Reconstituting microbiota-depleted mice with select SCFA-producing bacteria increased humoral responses in XX, but not XY, FCG mice. This XX-dependent enhancement appears to be independent of SCFA production in males, while female XX-dependent responses relied on SCFAs. FCG mice have been used to assess sex hormones and sex chromosome complements influences on various sexually dimorphic traits. The current study indicates that the gut microbiome impacts humoral responses in an XX-dependent manner, suggesting that the collaborative influence of gut bacteria and other sex-specific factors should be considered when interpreting data aimed at delineating the mechanisms that promote sexual dimorphisms.
2023-12-06 | GSE244866 | GEO
Project description:Abdominal aortic aneurysms (AAAs) are a prevalent and deadly human pathology with strong sexual dimorphism. Research demonstrates that sex hormones influence, but do not fully explain, male versus female AAA pathology. In addition to sex hormones, the X and Y sex chromosomes, and their unique complements of genes, may contribute to sexually dimorphic AAA pathology. Here, for the first time, we defined the effect of female (XX) versus male (XY) chromosome complement on AAA formation and rupture in phenotypically female mice using an established murine model. Abdominal aortas from female mice bearing the XY chromosome selectively expressed Y chromosome genes, while genes known to escape X-inactivation were higher in XX females. The majority of gene differences in XY females fell within inflammatory pathways. When XY females were infused with AngII, AAA incidences doubled and aneurysms ruptured. AAAs from XY females exhibited significant inflammation. Moreover, infusion of AngII to XY females augmented aortic activity of matrix metalloproteinases. Finally, testosterone exposure applied chronically, or as a single bolus at postnatal day 1, markedly worsened AAA outcomes in XY compared to XX females. These results demonstrate that an XY sex chromosome complement profoundly influences aortic gene expression profiles and promotes AAA severity.
2016-11-07 | GSE81580 | GEO
Project description:Objective-Aortic pathologies exhibit sexual dimorphism, with aneurysms in the ascending, thoracic and abdominal aorta (AAA) exhibiting higher prevalence in males. Despite lower incidence of aortic vascular disease in women, aneurysms progress rapidly. Mechanisms for these sex differences are unclear. We defined the role of sex chromosome complement and testosterone in regional development and progression of angiotensin II (AngII)-induced vascular pathologies. Approach and Results-We used transgenic male mice expressing Sry on an autosome to create low density lipoprotein receptor (Ldlr) deficient male mice with an XY or XX sex chromosome complement. Subjects were then sham operated or orcheictomized. Transcriptional profiling on abdominal aortas from XY or XX males demonstrated1746 genes influenced by sex chromosomes, sex hormones, or an interaction. A second cohort of animals was then infused with AngII for 28 days. Diffuse aortic aneurysm pathology developed in XY AngII-infused males, while XX males developed discrete AAAs. Castration reduced all AngII-induced aortic pathologies in XY and XX males. Thoracic aortas from AngII-infused XY males, but not XX males exhibited adventitial thickening. We infused male XY and XX mice with saline or AngII and quantified mRNA abundance of key genes in thoracic versus abdominal aortas. Regional differences in mRNA abundance existed before AngII infusions, which were differentially influenced by AngII between genotypes. Prolonged AngII infusions resulted in AAA aortic wall thickening in XY males with diffuse aortic pathology, while XX males had dilated focal AAAs. Conclusions-An XY sex chromosome complement mediates diffuse aortic pathology, while an XX sex chromosome complement contributes to discrete AngII-induced AAAs.
2018-07-22 | GSE102143 | GEO
Project description:Mammalian gonadal sex determination is dependent on proper expression of sex determining genes in fetal gonadal somatic support cells (i.e., pre-granulosa and pre-Sertoli cells in XX and XY gonads, resp.). We used a unique transgenic mouse strain combined with microarray profiling to identify all the differentially expressed transcripts in XX and XY isolated somatic support cells during critical stages of gonadal development and differentiation.
2009-11-09 | GSE18211 | GEO
Project description:To determine the role of sex chromsomes in sex differences of autoimmune disease, we used high throughput RNA sequencing to analyze the transciptomes of CD4+ T cells stimuated with anti-CD3/CD28 from XX and XY- mice using the “four core genotypes” mouse model. We found higher expression of several X genes in the XY- genotype compared to XX, suggesting a difference in DNA methylation of these genes between Xp and Xm. In a hypothesis driven targeted approach, we investigated two immunomodulatory X genes, Tlr7 and FoxP3 and found that the promoter regions of both genes had more DNA methylation on the Xp than Xm, and that both genes had higher expression in autoantigen stimulated CD4+ T cells from XY- compared to XX mice. This study provides new insights regarding how sex chromsomes affect gene expression and cause sex differences in autoimmune disease.
2019-12-10 | GSE139035 | GEO