A biopsy sample reduction approach to identify significant alterations of the testicular transcriptome in the presence of Y-chromosomal microdeletions that are independent of germ cell composition

Cappallo-Obermann, Heike; Kopylow, Kathrein von; Schulze, Wolfgang; Spiess, Andrej‐Nikolai

doi:10.1007/s00439-010-0865-9

Cited by 13 publications

(6 citation statements)

References 48 publications

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“…20 This observation suggests a central, regulatory role of the AZF gene products in spermatogenesis. Mutations of genes in the AZF regions themselves or in genes that regulate their expression would be expected to have significant downstream consequences.…”

Section: Discussionmentioning

confidence: 95%

Deletion or underexpression of the Y-chromosome genes CDY2 and HSFY is associated with maturation arrest in American men with nonobstructive azoospermia

Stahl¹,

Mielnik²,

Barbieri³

et al. 2012

Asian J Androl

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Maturation arrest (MA) refers to failure of germ cell development leading to clinical nonobstructive azoospermia. Although the azoospermic factor (AZF) region of the human Y chromosome is clearly implicated in some cases, thus far very little is known about which individual Y-chromosome genes are important for complete male germ cell development. We sought to identify single genes on the Y chromosome that may be implicated in the pathogenesis of nonobstructive azoospermia associated with MA in the American population. Genotype-phenotype analysis of 132 men with Y-chromosome microdeletions was performed. Protein-coding genes associated with MA were identified by visual analysis of a genotype-phenotype map. Genes associated with MA were selected as those genes within a segment of the Y chromosome that, when completely or partially deleted, were always associated with MA and absence of retrievable testicular sperm. Expression of each identified gene transcript was then measured with quantitative RT-PCR in testicular tissue from separate cohorts of patients with idiopathic MA and obstructive azoospermia. Ten candidate genes for association with MA were identified within an 8.4-Mb segment of the Y chromosome overlapping the AZFb region. CDY2 and HSFY were the only identified genes for which differences in expression were observed between the MA and obstructive azoospermia cohorts. Men with obstructive azoospermia had 12-fold higher relative expression of CDY2 transcript (1.3360.40 vs. 0.1160.04; P50.0003) and 16-fold higher expression of HSFY transcript (0.7860.32 vs. 0.0560.02; P50.0005) compared to men with MA. CDY2 and HSFY were also underexpressed in patients with Sertoli cell only syndrome. These data indicate that CDY2 and HSFY are located within a segment of the Y chromosome that is important for sperm maturation, and are underexpressed in testicular tissue derived from men with MA. These observations suggest that impairments in CDY2 or HSFY expression could be implicated in the pathogenesis of MA.

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Section: Discussionmentioning

confidence: 95%

Deletion or underexpression of the Y-chromosome genes CDY2 and HSFY is associated with maturation arrest in American men with nonobstructive azoospermia

Stahl¹,

Mielnik²,

Barbieri³

et al. 2012

Asian J Androl

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“…The highest number of differentially expressed miRNAs in SCOS might be due to the absence of germ cells in these samples. This was previously described as ‘germ cell effect’ where changes in the RNA expression in testicular biopsies with impaired spermatogenesis in fact reflect the germ cell composition of normal tissue (Cappallo‐Obermann et al ., ).…”

Section: Discussionmentioning

confidence: 97%

MicroRNA expression profiles in testicular biopsies of patients with impaired spermatogenesis

et al. 2016

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Spermatogenesis is a complex process that involves thousands of genes whose expression during different stages is strictly regulated. Small non-coding microRNAs play an important role in the posttranscriptional regulation of mRNA processing during spermatogenesis. Using Agilent SurePrint v16 microRNA 8 × 60 K microarray kit, we investigated the microRNA expression profiles of 24 formalin-fixed paraffin-embedded testicular biopsies from patients with hypospermatogenesis (n = 10), hypospermatogenesis and azoospermia factor c region on the Y chromosome (AZFc) deletion (n = 3), Sertoli cell-only syndrome (n = 3) and maturation arrest (n = 2), in comparison with subjects with normal spermatogenesis (n = 6). After adjusting for multiple testing, six deregulated miRNAs were detected in the patients with AZFc deletion, 30 in maturation arrest group, 52 in Sertoli cell-only syndrome group of patients, and none in the group of patients with hypospermatogenesis. Some of the deregulated microRNAs were shared between groups, resulting in 58 unique differentially expressed microRNAs. The expression of five microRNAs (hsa-miR-34b, hsa-miR-449b, hsa-miR-517c, hsa-miR-181c, and hsa-miR-605) was validated by qRT-PCR in a total of 74 samples. Using mRNA expression profiles of subjects with matching histopathological patterns of impaired spermatogenesis from publically available Gene Expression Omnibus data sets, we have performed integrated mRNA-microRNA regulatory network analysis. Pathway analysis revealed significantly enriched set of genes for tumor necrosis factor-related apoptosis-inducing ligand signaling pathway, previously shown to be involved in regulation of apoptosis in normal functioning testis. Our results should be considered as preliminary as we have analyzed only a small number of patients in each studied group. Further studies with larger number of patients with impaired spermatogenesis as well as more targeted approaches with parallel microRNA and mRNA expression profiling in isolated subpopulations of somatic or germ cells from different stages of spermatogenesis are needed to clarify the role of the microRNAs in the process of spermatogenesis.

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“…Only those datasets that were compliant with all the above-mentioned requirements were enrolled. In view of this, six datasets, namely, GSE45885 ( 20 ), GSE4797 ( 21 ), GSE6023 ( 22 ), GSE21613 ( 23 ), GSE9210 ( 24 ), and GSE145467 ( 25 ) were enrolled for further analysis. In other words, 38 OA testicular samples and 30 SCOS testicular samples were enrolled, and detailed information regarding these six datasets is listed in Supplementary Table S1 .…”

Section: Methodsmentioning

confidence: 99%

Aberrant Gene Expression Profiling in Men With Sertoli Cell-Only Syndrome

et al. 2022

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Sertoli cell-only syndrome (SCOS) is the most severe and common pathological type of non-obstructive azoospermia. The etiology of SCOS remains largely unknown to date despite a handful of studies reported in this area. According to the gene expression of testicular tissue samples in six datasets from the Gene Expression Omnibus, we detected 1441 differentially expressed genes (DEGs) between SCOS and obstructive azoospermia (OA) testicular tissue samples. Enriched GO terms and KEGG pathways for the downregulated genes included various terms and pathways related to cell cycle and reproduction, while the enrichment for the upregulated genes yielded many inflammation-related terms and pathways. In accordance with the protein-protein interaction (PPI) network, all genes in the most critical module belonged to the downregulated DEGs, and we obtained nine hub genes, including CCNB1, AURKA, CCNA2, BIRC5, TYMS, UBE2C, CDC20, TOP2A, and OIP5. Among these hub genes, six were also found in the most significant SCOS-specific module obtained from consensus module analysis. In addition, most of SCOS-specific modules did not have a consensus counterpart. Based on the downregulated genes, transcription factors (TFs) and kinases within the upstream regulatory network were predicted. Then, we compared the difference in infiltrating levels of immune cells between OA and SCOS samples and found a significantly higher degree of infiltration for most immune cells in SCOS than OA samples. Moreover, CD56bright natural killer cell was significantly associated with six hub genes. Enriched hallmark pathways in SCOS had remarkably more upregulated pathways than the downregulated ones. Collectively, we detected DEGs, significant modules, hub genes, upstream TFs and kinases, enriched downstream pathways, and infiltrated immune cells that might be specifically implicated in the pathogenesis of SCOS. These findings provide new insights into the pathogenesis of SCOS and fuel future advances in its theranostics.

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A biopsy sample reduction approach to identify significant alterations of the testicular transcriptome in the presence of Y-chromosomal microdeletions that are independent of germ cell composition

Cited by 13 publications

References 48 publications

Deletion or underexpression of the Y-chromosome genes CDY2 and HSFY is associated with maturation arrest in American men with nonobstructive azoospermia

Deletion or underexpression of the Y-chromosome genes CDY2 and HSFY is associated with maturation arrest in American men with nonobstructive azoospermia

MicroRNA expression profiles in testicular biopsies of patients with impaired spermatogenesis

Aberrant Gene Expression Profiling in Men With Sertoli Cell-Only Syndrome

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