Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1270148 | ENA |
REPOSITORIES: ENA
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Project description:Male infertility is an increasingly pressing global health concern, with abnormal spermiogenesis being a major cause of asthenoteratozoospermia. Although RNA-binding proteins (RBPs)-orchestrated alternative splicing has recently garnered significant attention, its regulation mechanisms during spermiogenesis remain unclear. Here, we identify hnRNPR as a crucial m6A-dependent splicing regulator. Mutations in hnRNPR lead to asthenoteratozoospermia in both humans and mice. Mechanistically, loss of hnRNPR exhibits widespread transcriptomic, proteomics, and m6A-modified splicing dysregulation, disrupting these genes essential for acrosome formation and flagellum development. Remarkably, Skap2 knockdown mice exhibit sperm defects that phenocopy those seen in Hnrnpr mutants. Importantly, therapeutic delivery of SKAP2, via extracellular vesicles, restores F-actin-mediated cytoskeletal integrity and improves sperm motility. Collectively, these findings establish that spermiogenesis is controlled post-transcriptionally by splicing in an m6A-dependent manner and reveal a promising therapeutic contribution for male infertility.
2025-06-04 | PXD064452 | Pride
Project description:Male infertility is an increasingly pressing global health concern, with abnormal spermiogenesis being a major cause of asthenoteratozoospermia. Although RNA-binding proteins (RBPs)-orchestrated alternative splicing has recently garnered significant attention, its regulation mechanisms during spermiogenesis remain unclear. Here, we identify hnRNPR as a crucial m6A-dependent splicing regulator. Mutations in hnRNPR lead to asthenoteratozoospermia in both humans and mice. Mechanistically, loss of hnRNPR exhibits widespread transcriptomic, proteomics, and m6A-modified splicing dysregulation, disrupting these genes essential for acrosome formation and flagellum development. Remarkably, Skap2 knockdown mice exhibit sperm defects that phenocopy those seen in Hnrnpr mutants. Importantly, therapeutic delivery of SKAP2, via extracellular vesicles, restores F-actin-mediated cytoskeletal integrity and improves sperm motility. Collectively, these findings establish that spermiogenesis is controlled post-transcriptionally by splicing in an m6A-dependent manner and reveal a promising therapeutic contribution for male infertility.
2025-06-10 | PXD064447 | Pride
Project description:Alternative splicing (AS) plays significant roles in fundamental biological activities. AS also are prevalent in the testis, but the regulations of alternative splicing in spermatogenesis is vague. Here, we report that Serine/arginine-rich splicing factor 1 (SRSF1), plays critical roles in alternative splicing and male reproduction. Male germ cell-specific deletion of Srsf1 led to complete infertility and abnormal spermatogenesis. We further demonstrated that Srsf1 is required for spermatogonial stem cell differentiation and mitotic-to-meiotic transition. Mechanistically, by combining RNA-seq data with LACE-seq data, we showed that SRSF1 regulatory networks have functions in spermatogenesis. Particularly, we found that SRSF1 affects the AS of Stra8 in a direct manner and Dazl, Dmc1, Mre11a, Syce2 and Rif1 in an indirect manner. Taken together, our findings demonstrate that SRSF1 has crucial functions in spermatogenesis and male fertility by regulating alternative splicing.
2024-03-31 | GSE226551 | GEO
Project description:Alternative splicing (AS) plays significant roles in fundamental biological activities. AS also are prevalent in the testis, but the regulations of alternative splicing in spermatogenesis is vague. Here, we report that Serine/arginine-rich splicing factor 1 (SRSF1), plays critical roles in alternative splicing and male reproduction. Male germ cell-specific deletion of Srsf1 led to complete infertility and abnormal spermatogenesis. We further demonstrated that Srsf1 is required for spermatogonial stem cell differentiation and mitotic-to-meiotic transition. Mechanistically, by combining RNA-seq data with LACE-seq data, we showed that SRSF1 regulatory networks have functions in spermatogenesis. Particularly, we found that SRSF1 affects the AS of Stra8 in a direct manner and Dazl, Dmc1, Mre11a, Syce2 and Rif1 in an indirect manner. Taken together, our findings demonstrate that SRSF1 has crucial functions in spermatogenesis and male fertility by regulating alternative splicing.
2024-03-31 | GSE226550 | GEO
Project description:Spermiogenesis defines the final phase of male germ cell differentiation. Multiple deubiquitinating enzymes have been linked to spermiogenesis, yet the impacts of deubiquitination on spermiogenesis remain poorly characterized. Here, we investigated the function of UAF1 in mouse spermiogenesis and male fertility. We selectively deleted Uaf1 in premeiotic germ cells using Stra8-Cre knock-in mouse strain (Uaf1 sKO), and found that Uaf1 is essential for spermiogenesis and male fertility. We found that UAF1 interacts and colocalizes with USP1 in testes. Conditional knockout of Uaf1 in testes results in disturbed expression and localization of USP1, suggesting that UAF1 regulates spermiogenesis through the function of the deubiquitinating enzyme USP1. We used tandem mass tag-based proteomics to identify differentially expressed proteins and potential underlying mechanisms, and found that conditional knockout Uaf1 in testes results in reduced levels of proteins essential for spermiogenesis. Thus, the UAF1/USP1 deubiquitinase complex is essential for normal spermiogenesis by regulating the levels of spermiogenesis-related proteins.
2024-02-07 | PXD046120 | Pride
Project description:In the mammalian testis, the pool of spermatogonia is amplified by mitosis before these progenitor germ cells undergo meiosis to generate the haploid cells that give rise to sperm. Extensive changes in the transcriptome accompany the onset of the pachytene stage of meiosis, including the transcriptional activation of meiotic genes, the pachytene piRNA pathway, as well as mRNAs required later during spermiogenesis. How transcription is regulated to ensure the precise timing of this major reprogramming of gene expression remains largely uncharacterized. Here, we report that the testis-specific transcription factor TCFL5 is initially activated by the transcription factor A-MYB during meiosis. Subsequently, A-MYB and TCFL5 mutually reinforce their own transcription establishing a central regulatory circuit that regulates meiosis and spermiogenesis, as well as mediates pachytene piRNA production. TCFL5 drives the transcription of 476 genes required for meiosis including genes encoding pachytene piRNA biogenesis proteins, and 796 genes required for spermiogenesis. Tcfl5−/− mutant mice are sterile and spermatogenesis arrests at the mid- or late-pachytene stage of meiosis. Intriguingly, Tcfl5 haploinsufficiency leads to reduced male fertility suggesting germ cells are sensitive to Tcfl5 dosage to develop. Compromised TCFL5 expression underlies the reduced fertility phenotype directly or indirectly through regulating other transcription factors in Tcfl5+/− mutant mice. TCFL5 drives the transcription of evolutionarily younger pachytene piRNAs, while A-MYB regulates older pachytene piRNAs. Older and younger piRNAs mutually initiate their own processing providing evidence how these selfish genetic elements hijack meiotic transcriptional network to amplify themselves. We also demonstrate that TCFL5-mediated regulation of male meiosis and piRNA production is conserved in macaque. Our data establish a direct role of TCFL5 in ensuring the simultaneous activation of genes required for meiosis and spermiogenesis in mammals.
2023-01-11 | GSE166104 | GEO
Project description:Co-transcriptional processing of nascent transcripts is coupled with transcription through the carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII). The mRNA modification N6-methyladenosine (m6A) occurs co-transcriptionally and impacts pre-mRNA processing. How alternative splicing of pre-mRNA is co-transcriptionally regulated in an m6A-dependent manner is not well understood. Furthermore, splicing regulation through RNAPII pausing has been frequently suggested but the underlying control mechanism remains unclear. Here, we show that the m6A reader protein hnRNPG directly binds to the phosphorylated CTD of RNAPII using Arg-Gly-Gly (RGG) motifs in its low-complexity region. This RGG-phospho-CTD interaction and nascent RNA binding by hnRNPG enables its co-transcriptional association with RNAPII, resulting in transcriptome-wide regulation of alternative splicing and transcript abundance. m6A sites near exon splice sites in nascent mRNA further modulate hnRNPG binding and exon splicing. Exon inclusion is associated with RNAPII pausing downstream of the m6A site. Our results reveal an integrated nuclear mechanism of m6A-mediated gene regulation, in which an m6A reader protein regulates gene expression by using RGG motifs to co-transcriptionally interact with both RNAPII and m6A-modified nascent pre-mRNA, while the interplay between hnRNPG binding and RNAPII pausing modulates alternative splicing regulation.
2019-09-05 | GSE114311 | GEO
Project description:Serine/arginine-rich splicing factor 2 (SRSF2), also known as SC35, is a member of a SRs protein family, which plays significant roles in numerous fundamental biological activities. However, the roles and underlying mechanisms of SRSF2 remain largely unclear during spermatogenesis. Here, we report that SRSF2 is involved in alternative splicing and that male germ cell-specific deletion of Srsf2 by Stra8-GFPCre causes absolute infertility and defective spermatogenesis. Further analyses revealed that deletion of Srsf2 in the male germ cells had harmful influences on the differentiation of spermatogonia and meiosis initiation. Mechanistically, by combining RNA-seq data with LACE-seq data, we showed that spermatogenesis, meiotic cell cycle, male gamete generation, reproductive development, and male sex differentiation were involved in the SRSF2 regulatory networks. Furthermore, SRSF2 affects expression and AS of Stra8, Stag3 and Atr in a direct manner, which were critical factors during spermatogenesis. Taken together, our results demonstrate that SRSF2 has important functions in spermatogenesis and male fertility by regulating alternative splicing.
2023-08-18 | GSE206536 | GEO
Project description:Serine/arginine-rich splicing factor 2 (SRSF2), also known as SC35, is a member of a SRs protein family, which plays significant roles in numerous fundamental biological activities. However, the roles and underlying mechanisms of SRSF2 remain largely unclear during spermatogenesis. Here, we report that SRSF2 is involved in alternative splicing and that male germ cell-specific deletion of Srsf2 by Stra8-GFPCre causes absolute infertility and defective spermatogenesis. Further analyses revealed that deletion of Srsf2 in the male germ cells had harmful influences on the differentiation of spermatogonia and meiosis initiation. Mechanistically, by combining RNA-seq data with LACE-seq data, we showed that spermatogenesis, meiotic cell cycle, male gamete generation, reproductive development, and male sex differentiation were involved in the SRSF2 regulatory networks. Furthermore, SRSF2 affects expression and AS of Stra8, Stag3 and Atr in a direct manner, which were critical factors during spermatogenesis. Taken together, our results demonstrate that SRSF2 has important functions in spermatogenesis and male fertility by regulating alternative splicing.
2023-08-18 | GSE206535 | GEO
Project description:Splicing factor ZRSR1 is known to have a role in spermatogenesis and fertility, leading its mutation to several reproductive defects in male. To investigate if Zrsr1 gene is involved in male reproductive control by the hypothalamus, we performed RNA-seq to determine the differences in gene expression, usage of isoforms and alternative splicing between the hypothalamus of WT mice and from Zrsr1mu mice.
2019-07-19 | E-MTAB-8012 | biostudies-arrayexpress