Transcriptomic differences between fibrotic and non-fibrotic testicular tissue reveal possible key players in Klinefelter syndrome-related testicular fibrosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE200680 | GEO | 2022/04/15
REPOSITORIES: GEO
Similar Datasets
Project description:Objective: Klinefelter Syndrome (KS) is the most common sexual chromosome abnormality (47,XXY) and represents the first genetic cause of male infertility. The mechanisms leading to KS testis degeneration are still unclear and no therapy is so far available for affected patients. The present study is aimed to unravel information about molecules playing a key role in the disruption of the spermatogenesis. Design: Gene expression profiles analysis of KS azoospermic testis versus normal testis, could provide useful information about the molecular basis of the alteration of the spermatogenesis. Materials and Methods: Transcriptome analysis was performed carrying out gene expression profile by a whole genome microarray approach on testis biopsies obtained from 6 azoospermic non-mosaic KS men and from 3 controls, for a total of 12 experiments. T-test and False Discovery Rate were used to evaluate differentially expressed genes. Identified transcripts were analysed by Ingenuity Pathways Analysis software to disclose genes biological functions. Results: Data analysis revealed the differentially up- and down-expression, in KS testis versus the control ones, of 656 and 247 genes related to Endocrine system development and function, Lipid metabolism, Reproductive disease, Free radical scavenging, and Cell death. Conclusions: Take together these data show the presence of several genes involved in testis microenvironment deregulation leading to the spermatogenesis failure. This information, associated with an early diagnosis could help to unravel possible therapeutic targets for testis failure prevention and limitation. Gene expression profile of 6 azoospermic KS testicular biopsies versus 3 pooled control testicular biposies form patients with normal spermatogenesis. A total of 12 experiments was carried out including biological and technical replicates.
2014-06-15 | E-GEOD-54023 | biostudies-arrayexpress
Project description:Transcriptomic differences between fibrotic and non-fibrotic testicular tissue reveal possible key players in Klinefelter syndrome-related testicular fibrosis
| PRJNA825978 | ENA
Project description:Objective: Klinefelter Syndrome (KS) is the most common sexual chromosome abnormality (47,XXY; 46,XY/47XXY) and represents the first genetic cause of male infertility. The mechanisms leading to KS testis degeneration are still unclear and no therapy is so far available for affected patients. The present study is aimed to unravel information about molecules playing a key role in the disruption of the spermatogenesis in mosaic oligospermic KS patients. Design: Gene expression profiles analysis of KS mosaic oligospermic testis versus normal testis, could provide useful information about the molecular basis of the alteration of the spermatogenesis. Materials and Methods: Transcriptome analysis was performed carrying out gene expression profile by a whole genome microarray approach on testis biopsies obtained from 3 oligopermic mosaic KS men and from 3 controls, for a total of 6 experiments. T-test and False Discovery Rate were used to evaluate differentially expressed genes. Identified transcripts were analysed by Ingenuity Pathways Analysis software to disclose genes biological functions. Results: Data analysis revealed the differentially up- and down-expression, in mosaic KS testis versus the control ones, of respectively 303 and 747 genes related to Endocrine system disorders, Lipid metabolism, Reproductive disease, cell and organ morphology, and cell death. Conclusions: Taken together these data show the presence of several de-regulated genes involved in mosaic KS testis failure. Data show the defects in sperm production and development and defects within the somatic component of the testis. This information, associated with an early diagnosis could help to unravel possible therapeutic targets for testis failure prevention and limitation.
2016-10-01 | GSE83989 | GEO
Project description:Objective: Klinefelter Syndrome (KS) is the most common sexual chromosome abnormality (47,XXY) and represents the first genetic cause of male infertility. The mechanisms leading to KS testis degeneration are still unclear and no therapy is so far available for affected patients. The present study is aimed to unravel information about molecules playing a key role in the disruption of the spermatogenesis. Design: Gene expression profiles analysis of KS azoospermic testis versus normal testis, could provide useful information about the molecular basis of the alteration of the spermatogenesis. Materials and Methods: Transcriptome analysis was performed carrying out gene expression profile by a whole genome microarray approach on testis biopsies obtained from 6 azoospermic non-mosaic KS men and from 3 controls, for a total of 12 experiments. T-test and False Discovery Rate were used to evaluate differentially expressed genes. Identified transcripts were analysed by Ingenuity Pathways Analysis software to disclose genes biological functions. Results: Data analysis revealed the differentially up- and down-expression, in KS testis versus the control ones, of 656 and 247 genes related to Endocrine system development and function, Lipid metabolism, Reproductive disease, Free radical scavenging, and Cell death. Conclusions: Take together these data show the presence of several genes involved in testis microenvironment deregulation leading to the spermatogenesis failure. This information, associated with an early diagnosis could help to unravel possible therapeutic targets for testis failure prevention and limitation.
2014-06-15 | GSE54023 | GEO
Project description:In humans, the most common sex chromosomal disorder is Klinefelter syndrome (KS), caused by the presence of one or more extra X-chromosomes. The KS patients display a diverse adult phenotype with increased height, gynaecomastia, and hypergonadotropic hypogonadism as the most common symptoms. Men with KS are almost always infertile due to testicular degeneration, which accelerates during puberty. Very few studies investigated the global gene expression analysis of adult KS testes and, more importantly, which cell types the differentially expressed transcripts originate from. Transcriptome analysis by RNA sequencing of fixed and paraffin embedded testes originating from 3 adult KS samples and 3 adult cellularity-matched controls revealed 236 differentially expressed transcripts in the adult KS testis. To examine the cellular origin of the differentially expressed transcripts, transcriptome profiling was also carried out on 4 testes with Sertoli Cell-Only and 4 testes with full spermatogenesis. Also, pre-pubertal KS and controls were RNA-sequenced.
2018-05-30 | GSE103905 | GEO
Project description:In humans, the most common sex chromosomal disorder is Klinefelter syndrome (KS), caused by the presence of one or more extra X-chromosomes. The KS patients display a diverse adult phenotype with increased height, gynaecomastia, and hypergonadotropic hypogonadism as the most common symptoms. Men with KS are almost always infertile due to testicular degeneration, which accelerates during puberty. Very few studies investigated when the germ cell loss begins and whether it is caused by dysgenetic fetal development of the testes. We investigated a series of fetal KS testis tissue samples and found a marked reduction in MAGE-A4-positive pre-spermatogonia in the developing KS gonads compared to controls, indicating a failure of the gonocytes to differentiate into pre-spermatogonia. Transcriptome analysis by RNA sequencing of formalin-fixed and paraffin embedded gonads originating from 4 fetal KS samples and 5 age- and cellularity-matched controls revealed 211 differentially expressed transcripts in the fetal KS testis. We found a significant enrichment of upregulated X-chromosomal transcripts and validated the expression of the pseudoautosomal region 1 (PAR1) gene, AKAP17A. Moreover, we found enrichment of long non-coding RNAs in the KS testes (e.g. LINC01569 and RP11-485F13.1). In conclusion, our data indicates that the testicular phenotype observed among adult men with KS is initiated already in fetal life by failure of the gonocyte differentiation into pre-spermatogonia, which could be due to aberrant expression of long non-coding RNAs.
2018-08-28 | GSE103613 | GEO
Project description:We have evaluated the transcriptome of different testicular cell types, including germ cells, at single cell level in a testicular biopsy of a man with Klinefelter syndrome (XXY karyotype)
2019-08-30 | GSE130151 | GEO
Project description:Klinefelter syndrome (KS), also known as 47,XXY, is characterized by a distinct set of physiological abnormalities, commonly including infertility. The molecular basis for Klinefelter-related infertility is still unclear, largely due to the cellular complexity of the testis and the intricate endocrine and paracrine signaling that regulates spermatogenesis. Here, we demonstrate an analysis framework for dissecting human testis pathology that uses comparative analysis of single-cell RNA-sequencing data from the biopsies of 13 human donors. By comparing donors from a range of ages and forms of infertility, we generate gene expression signatures that characterize normal testicular function and distinguish clinically distinct forms of male infertility. Unexpectedly, we identified a subpopulation of Sertoli cells within multiple cases of KS that lack transcription from the XIST locus, with the consequence of increased X-linked gene expression compared to all other KS cell populations. By systematic assessment of known signaling pathways, we identify 72 pathways potentially active in testis, dozens of which appear upregulated in KS. Altogether our data support a model of pathogenic changes in interstitial cells cascading from loss of X-inactivation in pubertal Sertoli cells, and nominate testicular GNRH1 as a dosage-sensitive factor secreted by Sertoli cells that may contribute to the process. Our findings demonstrate the value of comparative patient analysis in mapping genetic mechanisms of disease, and identify an epigenetic phenomenon in KS Sertoli cells that may prove important for understanding causes of infertility and sex chromosome evolution.
2021-09-26 | GSE169062 | GEO
Project description:In this study, we reprogrammed fibroblasts from two azoospermic Klinefelter syndrome (KS) patients, and two healthy male and one healthy female donor with an efficient integration-free method using episomal plasmids and laminin-521 (LN521). Whole genome transcriptomics analysis showed differentially expressed genes between KS and healthy male donors with enrichment in gene ontology (GO) terms associated with fertility, cardiovascular development, ossification and brain development, for both KS hiPSCs and fibroblasts, correlating with the KS clinical phenotype. Thorough XCI analysis combining transcriptomics data, RNA FISH and H3K27me3 staining, revealed skewed XCI in one KS fibroblast line and variability in XCI state of KS hiPSCs similar to female hiPSCs, showing either XaXi or XaXe status. Furthermore, we found up-regulated X-linked genes involved in nervous system development, synaptic transmission as well as metabolic processes supporting the potential use of KS derived hiPSC as an in vitro model for KS.
2019-10-05 | E-MTAB-7340 | biostudies-arrayexpress
Project description:Klinefelter syndrome (KS; 47,XXY) affects 1-2 in 1000 males. Most men with KS suffer from an early germ cell loss and testicular fibrosis from puberty onwards. Mechanisms responsible for these processes remain unknown. Previous genomics studies on testis tissue from men with KS focused on germ cell loss, while a transcriptomic analysis focused on testicular fibrosis has not yet been performed. This study aimed to identify factors involved in the fibrotic remodelling of KS testes by analysing the transcriptome of fibrotic and non-fibrotic testicular tissue. RNA sequencing was performed to compare the genes expressed in testicular samples with (KS and testis atrophy) and without (Sertoli cell-only syndrome and fertile controls) fibrosis (n = 5, each). Additionally, differentially expressed genes (DEGs) between KS and testis atrophy samples were studied to reveal KS-specific fibrotic genes. DEGs were considered significant when p < 0.01 and log2FC > 2. Next, downstream analyses (GO and KEGG) were performed. Lastly, RNA in situ hybridization was performed to validate the results. The first analysis (fibrotic vs non-fibrotic) resulted in 734 significant DEGs (167 up- and 567 down-regulated). Genes involved in the extracellular structure organization (e.g. VCAM1) were found up-regulated. KEGG analysis showed an up-regulation of genes involved in the TGF-β pathway. The KS vs testis atrophy analysis resulted in 539 significant DEGs (59 up- and 480 down-regulated). Chronic inflammatory response genes were found up-regulated. The overlap of X-linked DEGs from the two analyses revealed three genes: matrix-remodelling associated 5 (MXRA5), doublecortin (DCX) and variable charge X-Linked 3B (VCX3B). RNA in situ hybridization showed an overexpression of VCAM1, MXRA5 and DCX within the fibrotic group compared with the non-fibrotic group. To summarize, this study revealed DEGs between fibrotic and non-fibrotic testis tissue, including VCAM1. In addition, X-linked fibrotic genes were revealed, e.g. MXRA5, DCX and VCX3B. Their potential role in KS-related testicular fibrosis needs further study.
| S-EPMC9748020 | biostudies-literature