Transcriptome changes in patients with severely impaired spermatogenesis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE145467 | GEO | 2020/02/19
REPOSITORIES: GEO
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Project description:Transcriptome changes in patients with severely impaired spermatogenesis
| PRJNA607268 | ENA
Project description:In the present study we carried out testicular gene expression profiling of patients with AZFc microdeletion, idiopathic infertility and normal spermatogenesis, in order to identify up- and downregulated genes in the different conditions, and to verify the presence of specific molecular pathways leading to the spermatogenic damage in patients with AZFc deletions. All samples of patients with AZFc deletion clustered together, showing downregulation of several genes related to spermatogenesis. In this study, we analyzed testis expression profiles of 16 patients with different phenotypes, including men with AZFc deletions and men with idiopathic infertility. All pathological human testis RNAs were hybridized against normal testis reference RNA samples (obstructive azoospermia), while the three samples with normal spermatogenesis were hybridized against a control represented by an home-made RNA universal reference consisting of a commercial human purified tissue RNA pool (brain, liver, muscle and lung) (Clontech, Terra Bella, CA, USA) . These latter hybridizations were carried out in order to generate a profile of genes specifically expressed in normal testis.
2010-10-04 | E-GEOD-14310 | biostudies-arrayexpress
Project description:Temporal study of the first wave of spermatogenesis in juvenile mouse testis and analysis of four germ cell deficient mouse models.<br> A series of purified testis cell-types (McCarrey libraries)constituting a focussed gene set was exploited to examine gene expression in prepubertal mouse testis. Testis RNA from C57/BL6J mice at various ages post partum was compared to a common control consisting of adult (8 week) testis RNA from the same strain(also corresponding to the last time-point).This generates a time course showing the activation of genes on the array across the first wave of spermatogenesis, which can then be correlated with the appearance of specific germ cell types, allowing assignation of unknown genes to differing cell types. <br> <br> Adult testis RNA from four different genetic models of infertility (XXSxrb, mshi, Bax -/-, bs) were compared to age- and strain-matched normal control testis RNA. These models possess different cellular complements within the testis, which can be interpreted within the framework established by the first wave analysis and used to refine the assignment of genes to cell types.
2006-08-10 | E-MEXP-571 | biostudies-arrayexpress
Project description:Spermatogenesis, a fundamental process in male reproduction, is driven by an ordered series of events, which rely on the trafficking of specific proteins between nucleus and cytoplasm. The importin α family of proteins mediates movement of specific cargo proteins when bound to importin β. Importin α genes have distinct expression patterns in mouse testis, implying they may have unique roles during mammalian spermatogenesis. Here we use a loss-of-function approach to specifically determine the role of importin α7 (Kpna6) in spermatogenesis and male fertility. We show that ablation of importin α7 in male mice leads to infertility and has multiple cumulative effects on both germ cells and Sertoli cells culminating in oligozoospermia. Importin α7-deficient mice exhibit an impaired Sertoli cell function, including loss of Sertoli cells from the seminiferous epithelium and a compromised nuclear transport of the androgen receptor. Furthermore, our data demonstrate devastating defects in spermiogenesis that are accompanied by a disturbed histone-protamine-exchange in elongating spermatids, resulting in incomplete sperm maturation and a massive loss of sperms. Our work uncovers the essential role of importin α7 in spermatogenesis and hence in male fertility.
2021-09-20 | GSE160969 | GEO
Project description:Expression profiling of mouse ing2 -/- testis vs WT reveals gene expression differences consistent with spermatogenic arrest and infertility. Ing2 is indispensable for male germ cell development in mice. While mice deficient for Ing2 were born and grew without apparent abnormalities, male, but not female, were infertile, consistent with the highest expression of Ing2 in testes in wild-type mice and in humans. Histological and DNA content analyses in Ing2-/- testes revealed a spermatogenesis arrest at meiotic phase and enhanced apoptosis associated with increased p53, resulting in a decline in mature spermatozoa, which became more severe in older age. HDAC1 accumulation and core histone deacetylation at pachytene stage were impaired in Ing2-/- testes, suggesting that the recruitment of HDAC1 by Ing2 plays a critical role in spermatogenesis. This study establishes Ing2 as a novel mammalian regulator of spermatocyte differentiation, which coordinates spermatogenesis stage-specific histone modifications. This study has implications in understanding human male infertility. Testis from WT and Ing2 KO mice at 2-3 months of age where analyzed for differences in gene expression.
2010-11-19 | E-GEOD-18610 | biostudies-arrayexpress
Project description:Spermatogenesis is a complex multi-step process involving intricate interactions between different cell types in the male testis. Disruption of these interactions results in infertility. Combination of shotgun tissue proteomics with MALDI imaging mass spectrometry is markedly potent in revealing topological maps of molecular processes within tissues. Here, we use a combinatorial approach on a characterized mouse model of hormone induced male infertility to uncover misregulated pathways. Comparative testicular proteome of wildtype and mice overexpressing human P450 aromatase (AROM+) with pathologically increased estrogen levels unravels gross dysregulation of spermatogenesis and emergence of pro-inflammatory pathways in AROM+ testis. In situ MS allowed us to localize misregulated proteins/peptides to defined regions within the testis. Results suggest that infertility is associated with substantial loss of proteomic heterogeneity, which define distinct stages of seminiferous tubuli in healthy animals. Importantly, considerable loss of mitochondrial factors, proteins associated with late stages of spermatogenesis and steroidogenic factors characterise AROM+ mice. Thus, the novel proteomic approach pinpoints in unprecedented ways the disruption of normal processes in testis and provides a signature for male infertility.
2021-01-07 | PXD022870 | Pride
Project description:Spermatogenesis is the process by which spermatogonial stem cells differentiate into haploid spermatozoa. During this process, multiple testis-specific histone variants are involved in the dynamic chromatin transitions. H2BFWT is a testis-specific H2B variant only found in primates, and several reports showed that single-nucleotide polymorphisms (SNPs) of H2BFWT are associated with male non-obstructive infertility. Different from another testis-specific variant TH2B, H2BFWT is preferentially localized in sub-telomeric regions and the promoter regions of testicular high expression genes during the transition from differentiated spermatogonia to early spermatocytesspermatogenesis. Cryo-EM structural analysis shows that the H2BFWT nucleosome is defined by weakened interactions between H2A-H2BFWT dimer and H4, and between the histone octamer and DNA. WIn addition, we found that the shape of the H2A L1 loops was also changed by the presence of H2BFWT. Furthermore, our structural model shows that H2BFWTH100R, which is one of the SNPs associated with infertility, further destabilizes the nucleosome and increases the nucleosome unwrapping rate by interfering with the interaction with H4K91. Taken together, our results suggest that H2BFWT may be necessary for the regulation of spermatogenesis-related genes transcription in spermatogonia by decreasing RNA polymerase II transcription barriers, and that the H100R mutation overdrives its nucleosome-destabilizing effects which likely explain how it causes infertility.
2024-06-01 | GSE206260 | GEO
Project description:BackgroundIn the past 15 years, numerous studies have described aberrant DNA methylation of imprinted genes (e.g. MEST and H19) in sperm of oligozoospermic men, but the prevalence and genomic extent of abnormal methylation patterns have remained unknown.ResultsUsing deep bisulfite sequencing (DBS), we screened swim-up sperm samples from 40 normozoospermic and 93 patients diagnosed as oligoasthenoteratozoospermic, oligoteratozoospermic or oligozoospermic, which are termed OATs throughout the manuscript, for H19 and MEST methylation. Based on this screening, we defined three patient groups: normal controls (NC), abnormally methylated oligozoospermic (AMO; n = 7) and normally methylated oligozoospermic (NMO; n = 86). Whole-genome bisulfite sequencing (WGBS) of five NC and five AMO samples revealed abnormal methylation levels of all 50 imprinting control regions in each AMO sample. To investigate whether this finding reflected epigenetic germline mosaicism or the presence of residual somatic DNA, we made a genome-wide inventory of soma-germ cell-specific DNA methylation. We found that > 2000 germ cell-specific genes are promoter-methylated in blood and that AMO samples had abnormal methylation levels at these genes, consistent with the presence of somatic cell DNA. The comparison between the five NC and six NMO samples revealed 19 differentially methylated regions (DMRs), none of which could be validated in an independent cohort of 40 men. Previous studies reported a higher incidence of epimutations at single CpG sites in the CTCF-binding region 6 of H19 in infertile patients. DBS analysis of this locus, however, revealed an association between DNA methylation levels and genotype (rs2071094), but not fertility phenotype.ConclusionsOur results suggest that somatic DNA contamination and genetic variation confound methylation studies in sperm of infertile men. While we cannot exclude the existence of rare patients with slightly abnormal sperm methylation at non-recurrent CpG sites, the prevalence of aberrant methylation in swim-up purified sperm of infertile men has likely been overestimated, which is reassuring for patients undergoing assisted reproduction.
| S-EPMC7204326 | biostudies-literature
Project description:Spermatogenic cells express more alternatively spliced RNAs than most whole tissues; however, the regulation of these events remains unclear. Here we characterize the function of a testis-specific IQ motif containing H gene (Iqch), whose expression has been confirmed to be testis specific in all mammalian species analyzed yet its role remains elusive. Using a mutant mouse model, we found that Iqch is essential for the specific expression of RNA isoforms during spermatogenesis. Through immunohistochemistry of adult mouse testis, we noted that Iqch was localized in somatic and germ cells, including spermatogonia, spermatocytes and round spermatids. Further, Iqch was expressed mainly in the nucleus at the stages spermatocyte and spermatid, where IQCH appeared juxtaposed with SRRM2 and ERSP1, suggesting that interactions among these proteins regulate alternative splicing (AS). By RNA-seq, we noted that mutant Iqch produces alterations in gene expression, including the clear downregulation of testis-specific lncRNAs and protein coding genes at the spermatid stage, and AS modifications, principally increased intron retention, resulting in complete male infertility. Interestingly, the presence of WT Iqch allowed us to identify novel spliced transcripts, while mutant Iqch modified the expression and use of hundreds of RNA isoforms, favoring the expression of the canonical form. This suggests that Iqch is part of a splicing control mechanism, essential in germ cell biology. Our findings reveal the role of Iqch in spermatogenesis and provide clues to the molecular mechanisms controlling the expression of RNA isoforms, mainly in the last stages of spermatogenesis
2023-03-22 | GSE214201 | GEO
Project description:We tested whether the defects in spermatogenesis and increases in germ cell apoptosis that are induced by under-nutrition are associated with changes in mRNA expression and pre-mRNA alternative splicing in the testis. Groups of 8 male sheep were fed for a 10% increase or 10% decrease in body mass over 65 days. We identified 2,243 mRNAs, including TP53 and Claudin 11, that were differentially expressed in testis from underfed and well-fed sheep (FDR < 0.1), and found that their changes in expression were associated with germ cells, testis size, cell cycle and spermatogenesis variations. Furthermore, pairs of 269 mRNAs and 48 miRNAs were indentified based on target prediction and the negative regulatory effect of miRNAs on mRNA expression with functions involved in abnormal reproductive morphology, apoptosis and male infertility. Nutrition did not affect the total number of alternative splicing junctions, but affected 1,040 alternative splicing events (FDR < 0.05, ∆PSI > 10%). A total of 788 genes, including CREM, MAP2, HIPK3 and TRa2β, were differentially spliced between dietary treatments, with functions related to protein localization, cellular metabolic process, post-translational protein modification and spermatogenesis. In addition, three gene modules were positively correlated with spermatogenesis-related phenotypic traits and negatively related to apoptosis-related phenotypic traits. Among these gene modules, seven (CFLAR, PTPRC, F2R, MAP3K1, EPHA7, APP, BCAP31) were also differentially expressed between nutritional treatments, indicating their potential as markers of spermatogenesis or apoptosis. We conclude that under-nutrition causes changes in mRNAs and pre-mRNA alternative splicing that, at least partly, contribute to disrupted spermatogenesis and increased germ cell apoptosis.
2017-03-08 | GSE68274 | GEO