Loss of the importin Kpna2 causes infertility in male maice by disrupting the translocation of testis-specific transcription factors
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ABSTRACT:
PROVIDER: PRJNA880832 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21590900_1.fastq.gz | Fastqsanger.gz | |||
| SRR21590900_2.fastq.gz | Fastqsanger.gz | |||
| SRR21590901_1.fastq.gz | Fastqsanger.gz | |||
| SRR21590901_2.fastq.gz | Fastqsanger.gz | |||
| SRR21590902_1.fastq.gz | Fastqsanger.gz |
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Project description:Karyopherin proteins mediate the movement between the nucleus and cytoplasm of specific proteins that are essential for spermatogenesis. Through a loss-of-function approach, we here examine the specific role of Karyopherin Subunit Alpha 2 (Kpna2) in spermatogenesis and male fertility. The factors determined were (i) the spatial distribution of KPNA2 in the testis using immunofluorescence; (ii) the morphological and functional consequences of Kpna2 deficiency in terms of sperm production, quality, and motility, and fertility in knock-out and wild-type mice; and (iii) the transcriptomic consequences of Kpna2 deficiency in knock-out compared to wild-type mice by RNA-seq analysis. KPNA2 was found expressed in the cytoplasm of primary spermatocytes and the nucleus and cytoplasm of secondary spermatocytes and spermatid cells. Ablation of Kpna2 in male mice reduced their size, affected sperm motility, increased sperm abnormalities, and led to dysregulation of testis gene expression and ultimately to infertility. Impaired mRNA expression mainly affected clusters of genes expressed in spermatids and spermatocytes. Downregulated genes include a set of genes that participate in cell adhesion, extracellular matrix (ECM) organization, and ECM-receptor interaction. We detected the enrichment of some transcription factors that bind to regions around transcription start sites of downregulated genes. We propose an essential role of Kpna2 in spermatogenesis via the disrupted translocation of testis specific transcription factors that control the expression of genes related to ECM organization in the seminiferous tubules.
2023-07-19 | GSE213442 | GEO
Project description:Importin α7 deficiency causes infertility in male mice by disrupting spermatogenesis
| PRJNA675014 | ENA
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:The circadian clock in mammalian cells is cell-autonomously generated during the cellular differentiation process, but the underlying mechanisms are not understood. Here we show that perturbation of transcriptional program by constitutive expression of c-Myc and Dnmt1 ablation disrupts the differentiation-coupled emergence of the clock from mouse embryonic stem cells (ESCs). Using these model ESCs, 484 genes are identified by global gene expression analysis as correlating factors with differentiation-coupled circadian clock development. Among them, we find the misregulation of Kpna2 (Importin-alpha2) during the differentiation of the c-Myc over-expressed and Dnmt1-/- ESCs, in which sustaining cytoplasmic accumulation of PER proteins is observed. Moreover, constitutive expression of Kpna2 during the differentiation culture of ESCs significantly impairs clock development and KPNA2 facilitates cytoplasmic localization of PER1/2. These results suggest that the programmed gene expression network regulates the differentiation-coupled circadian clock development in mammalian cells, at least in part via post-transcriptional regulation of clock proteins.
2014-11-13 | GSE61184 | GEO
Project description:The circadian clock in mammalian cells is cell-autonomously generated during the cellular differentiation process, but the underlying mechanisms are not understood. Here we show that perturbation of transcriptional program by constitutive expression of c-Myc and Dnmt1 ablation disrupts the differentiation-coupled emergence of the clock from mouse embryonic stem cells (ESCs). Using these model ESCs, 484 genes are identified by global gene expression analysis as factors correlated with differentiation-coupled circadian clock development. Among them, we find the misregulation of Kpna2 (Importin-α2) during the differentiation of the c-Myc over-expressed and Dnmt1-/- ESCs, in which sustained cytoplasmic accumulation of PER proteins is observed. Moreover, constitutive expression of Kpna2 during the differentiation culture of ESCs significantly impairs clock development and KPNA2 facilitates cytoplasmic localization of PER1/2. These results suggest that the programmed gene expression network regulates the differentiation-coupled circadian clock development in mammalian cells, at least in part via post-transcriptional regulation of clock proteins.
2014-11-13 | GSE61096 | GEO
Project description:Karyopherin α 2 (KPNA2, importin α1) is involved in the nuclear import of proteins and participates in cellular processes and accumulates in the nucleus under cellular stresses including hydrogen peroxide-indeced oxidative stress via unknown mechanisms. We performed the immunoprecipitation assay and SILAC-based quantitative proteomic analysis in HeLa cells to reveal that hydrogen peroxide decreased the phosphorylation of KPNA2 at serine 62 (S62) and increased its interaction with nucleophosmin 1 (NPM1). Specifically, a reduction in phosphorylated S62 on KPNA2 was observed in the cytoplasmic fraction, but this phosphorylated KPNA2 was not detected in the nuclear fraction. We also identified fifty-four KPNA2-interacting proteins in the nuclear fraction. Among them, NPM1, RPLP0, and MYH9 interacted with KPNA2 in cells exposed to hydrogen peroxide but not in unstressed control cells. Furthermore, the subcellular fractionation, immunoprecipitation, western blotting, immunofluorescence assay, and qRT-PCR analyses were used to support a novel finding that S62 phosphorylation maintains KPNA2 in the cytoplasm, and hydrogen peroxide reduces the phosphorylation of KPNA2 S62 to promote KPNA2-NPM1 complex nuclear entry for gene regulation.
2024-10-17 | PXD051121 | Pride
Project description:To test whether nuclear importin alpha2 can regulate transcription, we sought to examine gene expression changes in cells with nuclear accumulation of importin alpha2 by performing microarray analysis. We designed an experiment in which EGFP-fused full-length importin alpha2 was transfected into HeLa cells. To exclude the possibility that exogenous, full-length importin alpha2 protein enhances nuclear transport of karyophilic proteins such as transcription factors and thereby directly influences gene expression, a mutant of importin alpha2 which is mutated in the C-terminal CAS-binding domain was also transfected, so that it is never recycled to the cytoplasm and shows complete nuclear localization. We undertook to investigate whether there were changes in gene expression common to cells expressing the full-length importin alpha2 and the C-terminal mutant (C-mutant) isoform. EGFP vs. EGFP-importin alpha2 full length, or EGFP vs EGFP-importin alpha2 CAS-binding mutant. One replicate each. EGFP-expressing cells are used as a control.
2010-11-24 | E-GEOD-25303 | biostudies-arrayexpress
Project description:To test whether nuclear importin alpha2 can regulate transcription, we sought to examine gene expression changes in cells with nuclear accumulation of importin alpha2 by performing microarray analysis. We designed an experiment in which EGFP-fused full-length importin alpha2 was transfected into HeLa cells. To exclude the possibility that exogenous, full-length importin alpha2 protein enhances nuclear transport of karyophilic proteins such as transcription factors and thereby directly influences gene expression, a mutant of importin alpha2 which is mutated in the C-terminal CAS-binding domain was also transfected, so that it is never recycled to the cytoplasm and shows complete nuclear localization. We undertook to investigate whether there were changes in gene expression common to cells expressing the full-length importin alpha2 and the C-terminal mutant (C-mutant) isoform.
2010-11-24 | GSE25303 | GEO
Project description:RNA binding proteins (RBPs) took a critical part in genome regulation. kpna2, as an essential member of the RBP family, was found to be highly expressed and associated with lymph node metastasis in gastric cancer (GC). Transcriptional sequencing data were used to find that KPNA2 primarily regulated alternative 5' splice site (A5SS), alternative 3'splice site (A3SS), exon skipping (ES) and cassette exon. Vitally, KPNA2 was involved in the transcriptional regulation of cancer-related genes. Therefore, we screened potential targets in AGS cells with differential expression and alternative splicing (AS) levels regulated by KPNA2, further identifying that KPNA2 was engaged in biological processes concerning immune response, cell proliferation and apoptosis in GC through transcriptional regulation. Besides, the binding sites of KPNA2 to spliceosomes were identified using improved RNA immunoprecipitation sequencing techniques, and KPNA2 was preferentially bound to the intron region. Notably, KPNA2 regulated the A3SS AS mode of WDR62, which may increase the malignancy of GC. Finally, we also discovered that AS of immune-related molecules can be regulated by KPNA2. Overall, for the first time, our results demonstrated that KPNA2 served as an oncogenic splicing factor in GC regulating AS and differential expression of GC-related genes and may represent a potential target for GC therap
2024-08-02 | GSE201419 | GEO
Project description:RNA binding proteins (RBPs) took a critical part in genome regulation. kpna2, as an essential member of the RBP family, was found to be highly expressed and associated with lymph node metastasis in gastric cancer (GC). Transcriptional sequencing data were used to find that KPNA2 primarily regulated alternative 5' splice site (A5SS), alternative 3'splice site (A3SS), exon skipping (ES) and cassette exon. Vitally, KPNA2 was involved in the transcriptional regulation of cancer-related genes. Therefore, we screened potential targets in AGS cells with differential expression and alternative splicing (AS) levels regulated by KPNA2, further identifying that KPNA2 was engaged in biological processes concerning immune response, cell proliferation and apoptosis in GC through transcriptional regulation. Besides, the binding sites of KPNA2 to spliceosomes were identified using improved RNA immunoprecipitation sequencing techniques, and KPNA2 was preferentially bound to the intron region. Notably, KPNA2 regulated the A3SS AS mode of WDR62, which may increase the malignancy of GC. Finally, we also discovered that AS of immune-related molecules can be regulated by KPNA2. Overall, for the first time, our results demonstrated that KPNA2 served as an oncogenic splicing factor in GC regulating AS and differential expression of GC-related genes and may represent a potential target for GC therap
2024-08-02 | GSE201418 | GEO