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Transcriptome analysis of fetal Klinefelter testis tissue samples compared to controls

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103613 | GEO | 2018/08/28

REPOSITORIES: GEO

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Project description:The piRNA pathway is studied in great detail in Drosophila female germline. In this study we show that unlike the female germline where all Piwi proteins are expressed throughout oogenesis, Ago3 - a Piwi family protein shows a spatial expression male germline. To understand dynamics of piRNA pathway during spermatogonia and primary spermatocyte stages of male germline development, we used arrest mutants. The bag of marbles (bam) and benign gonial cell neoplasm (bgcn) mutants have only early mitotic dividing germline cells in the testes due to failure to progress to primary spermatocyte stage, the cannonball (can) and spermatocyte arrest (sa) mutant germline cells cannot progress beyond primary spermatocyte stage. To investigate the dynamics of the piRNA pathway during spermatogenesis in spermatogonia and primary spermatocyte stages, we used testicular tissues from these stage-specific arrested mutants. While we used entire bam and bgcn mutant testes for spermatogonia purification, we while we manually removed the apical regions of can and sa mutant testes to exclude mitotically dividing undifferentiated germline cells for primary spermatocytes purification. Our results show that piRNAs mapping to transposons are more abundant in spermatogonia, whereas those mapping to Suppressor of Stellate [Su(Ste)] and AT-chX are mostly expressed in primary spermatocytes. Furthermore we observed that transposon-mapping piRNAs with ping-pong signature are more abundant in spermatogonia albeit still detectable in primary spermatocytes where Ago3 is not expressed. These results suggest that robust piRNA production via ping-pong cycle takes place in spermatogonia, and to a lesser extent in primary spermatocytes even in the absence of Ago3. Consistently, piRNAs from ago3 mutant testes also exhibit the ping-pong signature, confirming that a non-canonical ping-pong cycle is acting during spermatogenesis. Our study provides a developmental dimension to the piRNA pathway and uncovers a new mechanism used in the male germline to silence transposons. The difference in piRNA from spermatogonia and primary spermatocyte stages was studied by comparing small RNAs from bam and bgcn mutant testis, which represent spermatogonia stages with the small RNAs from apex removed can and sa testis, representing primary spermatocyte stages. In the study we also studied effect of loss of Piwi family proteins Aub and Ago3, which have different spatial expression during male germline development.

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Transcriptome analysis of fetal Klinefelter testis tissue samples compared to controls

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