Transcriptomic analysis of monosomy X (45,X) tissues during early human fetal and placental development
Ontology highlight
ABSTRACT: Bulk RNA sequencing data from human monosomy X (45,X) fetal tissues between 11 to 15 weeks post conception with age and tissue matched 46,XX and 46,XY controls. There are 96 files in total. Tissues include pancreas, liver, kidney, skin, mixed group (comprising of brain, heart, lung and spleen), placenta and muscle.
Project description:The dataset contains RNA-seq for 32 human fetal adrenal gland samples between 7 weeks post-conception (wpc) and 11.5 wpc and 14 control samples from different tissues across the same time frame. The study is designed with 8 fetal adrenal samples (4 of 46,XY; 4 of 46,XX) at 7wpc, 8wpc, 9wpc, 11.5wpc
Project description:The dataset contains RNA-seq for 32 human fetal brain cortex samples between 7 weeks post-conception (wpc) and 11.5 wpc and 14 control samples from different tissues across the same time frame. The study is designed with 8 fetal adrenal samples (4 of 46,XY; 4 of 46,XX) at 7wpc, 8wpc, 9wpc, 11.5wpc
Project description:Gene modified autologous hematopoietic stem cells (HSC) can provide significant clinical benefits to patients suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two patients treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both patients exhibited silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of EVI1. One patient died from overwhelming sepsis 27 months after gene therapy, whereas a second patient underwent an allogeneic HSC transplantation. Our data shows that forced overexpression of MDS1/EVI1 or EVI1 in human cells disrupts normal centrosome duplication, linking MDS1/EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression towards myelodysplasia.
Project description:Aneuploidies of human chromosome 21 (Down syndrome (DS) and monosomy 21 (M21)) lead to variable physiological abnormalities with constant mental retardation, locomotor deficits and altered muscle tone. To search for dosage-sensitive genes involved in DS and M21 phenotypes, we created two new mouse models carrying either tandem duplication (Ts2Yah) or a deletion (Ms3Yah) of the Stch-App interval homologous and syntenic with 21q11.2-q21.3 in humans. Here we report the complex mirror phenotypes of the trisomy and monosomy involving locomotion, muscle strength, mass and energetic balance that vary while ageing. Expression profiling of skeletal muscles revealed global changes in the expression of genes implicated in energetic metabolism, mitochondrial activity and biogenesis with down-regulation in Ts2Yah and up-regulation in Ms3Yah mice. The shift in skeletal muscle metabolism correlated with a change in mitochondrial proliferation without an alteration of the respiratory function. However ROS production from mitochondrial complex I decreased in Ms3Yah mice while membrane permeability of Ts2Yah mitochondria slightly increased. Our results clearly demonstrate the central versus peripheral impact of the variation of copy number of the Stch-App region on the locomotor activity, muscle biology and mitochondrial biogenesis in models of these aneuploidies.
Project description:Monosomy X (45,X) is associated with Turner syndrome and pregnancy loss in humans, but the underlying mechanisms remain unclear. We therefore undertook an exploratory study of the transcriptomic landscape of clinically relevant human fetal 45,X tissues (including pancreas, liver, kidney, skin, placenta) with matched 46,XX and 46,XY control samples between 11 and 15 weeks post conception (n = 78). Although most pseudoautosomal region 1 (PAR1) genes are lower in monosomy X tissues, we also found reduced expression of several key genes escaping X inactivation (e.g., KDM5C and KDM6A), several ancestral X-Y gene pairs, and potentially clinically important transcripts such as genes implicated in ascending aortic aneurysm. In contrast, higher expression of an autosomal, long non-coding RNA (OVCH1-AS1) is seen in all 45,X tissues. In the placenta, lower expression of CSF2RA is demonstrated, likely contributing to immune dysregulation. Taken together, these findings provide insights into the biological consequences of a single X chromosome during early human development and potential insights in genetic mechanisms in Turner syndrome.
Project description:In this case report, we highlight the practical dilemma, i.e. to perform ovarian tissue cryopreservation surgery in a 45, X Turner Syndrome patient or not, by reporting on the presence of follicles in a 13-year-old female diagnosed with 45, X monosomy and an unmeasurable anti-müllerian hormone serum level. We compare our results with previous research, highlight the challenges we faced in this case and provide recommendations for daily practice. Hereby, we demonstrate that excluding certain subgroups of Turner Syndrome patients (e.g. monosomy patients, and/or girls with an anti-müllerian hormone level below 2.0 ng/l) may be premature, especially based on the current state of published research data. This practical example of a challenging dilemma in the counselling of Turner Syndrome patients for fertility preservation is of interest for clinicians involved in fertility counselling and Turner Syndrome care.
Project description:Aneuploidies of human chromosome 21 (Down syndrome (DS) and monosomy 21 (M21)) lead to variable physiological abnormalities with constant mental retardation, locomotor deficits and altered muscle tone. To search for dosage-sensitive genes involved in DS and M21 phenotypes, we created two new mouse models carrying either tandem duplication (Ts2Yah) or a deletion (Ms3Yah) of the Stch-App interval homologous and syntenic with 21q11.2-q21.3 in humans. Here we report the complex mirror phenotypes of the trisomy and monosomy involving locomotion, muscle strength, mass and energetic balance that vary while ageing. Expression profiling of skeletal muscles revealed global changes in the expression of genes implicated in energetic metabolism, mitochondrial activity and biogenesis with down-regulation in Ts2Yah and up-regulation in Ms3Yah mice. The shift in skeletal muscle metabolism correlated with a change in mitochondrial proliferation without an alteration of the respiratory function. However ROS production from mitochondrial complex I decreased in Ms3Yah mice while membrane permeability of Ts2Yah mitochondria slightly increased. Our results clearly demonstrate the central versus peripheral impact of the variation of copy number of the Stch-App region on the locomotor activity, muscle biology and mitochondrial biogenesis in models of these aneuploidies. Total RNA isolated from gastrocnemius muscles of mice that are trisomic (Ts2Yah) and monosomic (Ms3Yah) for the Stch-App region on Mmu16 and diploid control mice
Project description:Mammalian sex chromosomes encode homologous X/Y gene pairs that were retained on the male Y and escape X chromosome inactivation (XCI) in females. Inferred to reflect X/Y-pair dosage sensitivity, monosomy X is a leading cause of miscarriage in humans with near full penetrance. This phenotype is shared with many other mammals but not the mouse, which offers sophisticated genetic tools to generate sex chromosomal aneuploidy but also tolerates its developmental impact. To address this critical gap, we generated X-monosomic human induced pluripotent stem cells (hiPSCs) alongside otherwise isogenic euploid controls from male and female mosaic samples. Phased genomic variants of these hiPSC panels enable systematic investigation of X/Y dosage-sensitive features using in vitro models of human development. Here, we demonstrate the utility of these validated hiPSC lines to test how X/Y-linked gene dosage impacts a widely-used model for the human syncytiotrophoblast. While these isogenic panels trigger a GATA2/3 and TFAP2A/C -driven trophoblast gene circuit irrespective of karyotype, differential expression implicates monosomy X in altered levels of placental genes, and in secretion of placental growth factor (PlGF) and human chorionic gonadotropin (hCG). Remarkably, weighted gene co-expression network modules that significantly reflect these changes are also preserved in first-trimester chorionic villi and term placenta. Our results suggest monosomy X may skew trophoblast cell type composition and function, and that the compound haploinsufficiency of the pseudoautosomal region likely plays a key role in these changes.
Project description:Mammalian sex chromosomes encode homologous X/Y gene pairs that were retained on the male Y and escape X chromosome inactivation (XCI) in females. Inferred to reflect X/Y-pair dosage sensitivity, monosomy X is a leading cause of miscarriage in humans with near full penetrance. This phenotype is shared with many other mammals but not the mouse, which offers sophisticated genetic tools to generate sex chromosomal aneuploidy but also tolerates its developmental impact. To address this critical gap, we generated X-monosomic human induced pluripotent stem cells (hiPSCs) alongside otherwise isogenic euploid controls from male and female mosaic samples. Phased genomic variants of these hiPSC panels enable systematic investigation of X/Y dosage-sensitive features using in vitro models of human development. Here, we demonstrate the utility of these validated hiPSC lines to test how X/Y-linked gene dosage impacts a widely-used model for the human syncytiotrophoblast. While these isogenic panels trigger a GATA2/3 and TFAP2A/C -driven trophoblast gene circuit irrespective of karyotype, differential expression implicates monosomy X in altered levels of placental genes, and in secretion of placental growth factor (PlGF) and human chorionic gonadotropin (hCG). Remarkably, weighted gene co-expression network modules that significantly reflect these changes are also preserved in first-trimester chorionic villi and term placenta. Our results suggest monosomy X may skew trophoblast cell type composition and function, and that the compound haploinsufficiency of the pseudoautosomal region likely plays a key role in these changes.