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RNA Immunoprecipitation(RIP)-seq of BUD31 in the mouse reproductive system

ABSTRACT: The testis is the organ with the most transcriptome diversity and alternative splicing (AS) is considered to be the most important source. However, the physiological role of AS in spermatogenesis is poorly understood. Here, we report that spliceosome component BUD31 is a prominent AS regulator in early stage of spermatogenesis in mice. Bud31 expression in the testis is initiated soon after birth. Conditional knock out of Bud31 in germ cells in Vasa-Cre mice led to loss of spermatogonial stem cells (SSCs) and to infertility. We further demonstrate that BUD31was required for both SSC pool maintenance and initiation of spermatogenesis. Mechanistically, BUD31 regulates the alternative splicing of multiple genes involved in cell cycle checkpoint and cell differentiation. In particular, we identified CDK2 as a direct splicing target of BUD31 through integrative analysis of SMART-seq and RIP-seq data. Knockout of BUD31 results in the intron retention as well as exon skipping of CDK2, which led to decrease in CDK2 expression. Our findings highlight the significance of BUD31 and its regulated AS in SSC self-renewal and differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE189715 | GEO | 2022/11/04

REPOSITORIES: GEO

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RNA sequencing (RNA-SEQ) of BUD31 knockout by cre-loxp in the mouse reproductive system

Project description:The testis is the organ with the most transcriptome diversity and alternative splicing (AS) is considered to be the most important source. However, the physiological role of AS in spermatogenesis is poorly understood. Here, we report that spliceosome component BUD31 is a prominent AS regulator in early stage of spermatogenesis in mice. Bud31 expression in the testis is initiated soon after birth. Conditional knock out of Bud31 in germ cells in Vasa-Cre mice led to loss of spermatogonial stem cells (SSCs) and to infertility. We further demonstrate that BUD31was required for both SSC pool maintenance and initiation of spermatogenesis. Mechanistically, BUD31 regulates the alternative splicing of multiple genes involved in cell cycle checkpoint and cell differentiation. In particular, we identified CDK2 as a direct splicing target of BUD31 through integrative analysis of SMART-seq and RIP-seq data. Knockout of BUD31 results in the intron retention as well as exon skipping of CDK2, which led to decrease in CDK2 expression. Our findings highlight the significance of BUD31 and its regulated AS in SSC self-renewal and differentiation.

2022-11-04 | GSE189714 | GEO

SpyCLIP sequencing of BUD31 in ovarian cancer cells

Project description:Mis-regulation of splicing factors are thought to activate cancer specific splicing programs that contribute to cancer development and progression. However, it remains a major challenge to identify the key splicing variants caused by aberrant expression of splicing factors in cancer. Here we report that splicing factor BUD31 is commonly overexpressed in high-grade serous ovarian carcinoma (HGSOC) and high level of BUD31 is associated with poor prognosis. RNA-seq analysis reveals that BUD31 inhibition predominantly results in alternation of exon skipping and intron retention. We further identify binding motif and preferred genome-wide binding pattern of BUD31 by CLIP-seq analysis. Our data indicate that BUD31 is a critical oncogenic splicing factor in ovarian cancer and might act as a potential therapeutic target.

2022-09-19 | GSE183451 | GEO

RNA immunoprecipitation sequencing (RIP-seq) of BUD31 in ovarian cancer cells

Project description:Mis-regulation of splicing factors are thought to activate cancer specific splicing programs that contribute to cancer development and progression. However, it remains a major challenge to identify the key splicing variants caused by aberrant expression of splicing factors in cancer. Here we report that splicing factor BUD31 is commonly overexpressed in high-grade serous ovarian carcinoma (HGSOC) and high level of BUD31 is associated with poor prognosis. RNA-seq analysis reveals that BUD31 inhibition predominantly results in alternation of exon skipping and intron retention. RNA immunoprecipitation sequencing (RIP-seq) was used to analysis the interaction between BUD31 and the target RNA. Our data indicate that BUD31 is a critical oncogenic splicing factor in ovarian cancer and might act as a potential therapeutic target.

2022-09-19 | GSE183450 | GEO

RNA sequencing (RNA-seq) of BUD31 knockdown or overexpression in ovarian cancer cells

Project description:Mis-regulation of splicing factors are thought to activate cancer specific splicing programs that contribute to cancer development and progression. However, it remains a major challenge to identify the key splicing variants caused by aberrant expression of splicing factors in cancer. Here we report that splicing factor BUD31 is commonly overexpressed in high-grade serous ovarian carcinoma (HGSOC) and high level of BUD31 is associated with poor prognosis. RNA-seq analysis reveals that BUD31 inhibition predominantly results in alternation of exon skipping and intron retention. We further identify binding motif and preferred genome-wide binding pattern of BUD31 by CLIP-seq analysis. In particular, we demonstrate that BUD31 overexpression drives an oncogenic splicing switch of BCL2L12 (an anti-apoptotic BCL2 family member) to produce a full-length isoform (BCL2L12-L) which in turn increased the survival, proliferation and anti-apoptosis ability of ovarian cancer cells. Our data indicate that BUD31 is a critical oncogenic splicing factor in ovarian cancer and might act as a potential therapeutic target.

2022-09-19 | GSE183449 | GEO

SRSF1-mediated alternative splicing is required for spermatogonial stem cell differentiation and mitotic-to-meiotic transition [LACE-seq]

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

SRSF1-mediated alternative splicing is required for spermatogonial stem cell differentiation and mitotic-to-meiotic transition [RNA-Seq]

2024-03-31 | GSE226550 | GEO

Splicing factor SRSF1 is essential for homing of precursor spermatogonial stem cells in mice

Project description:Spermatogonial stem cells (SSCs) provide a continuous spermatogenesis and male fertility. However, the underlying mechanisms of alternative splicing (AS) in mouse SSCs are still largely unclear. We demonstrated that SRSF1 is essential for gene expression and splicing in mouse SSCs. Specific deletion of Srsf1 in mouse germ cells impairs self-renewal and homing of SSCs leading to male infertility. Whole-mount staining data showed the absence of germ cells in the testes of adult cKO mice, which indicates severe non-obstructive azoospermia (NOA) in cKO mice. Expression of SSC-related genes (Gfra1, Pou5f1, Plzf, Dnd1, Stra8, and Taf4b) was significantly reduced in the testes of conditional knockout (cKO) mice. CLIP-seq data found that SSC-related genes (Plzf, Id4, Setdb1, Stra8, Tial1, Bcas2, Ddx5, Srsf10, Uhrf1, and Bud31) were bound by SRSF1 in the mouse testes. Moreover, multi-omics analysis suggests that SRSF1 directly binds and regulates the expression of Tial1 via AS to implement SSCs self-renewal and differentiation. Collectively, our data reveal the critical role of an SRSF1-mediated AS in SSCs self-renewal and differentiation, which may provide a framework to elucidate the molecular mechanisms of the post-transcriptional network underlying SSCs.

2024-01-08 | GSE227575 | GEO

Expression changes in mRNA expression associated with the effects of nutrition on apoptosis and spermatogenesis in the adult testis

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

Transcriptomic profiling of young and aged spermatogonial stem cells (RNA-Seq)

Project description:Spermatogonial stem cells (SSC), the foundation of spermatogenesis and male fertility, possess lifelong self-renewal activity. Aging leads to the decline in stem cell function and increased risk of paternal age-related genetic diseases. In the present study, we performed a comparative genomic analysis of mouse SSC (Oct4-GFP+/KIT-) and differentiating progenitors (Oct4-GFP+/KIT+) isolated from young and aged testes. Our transcriptome data revealed enormous complexity of expressed coding and non-coding RNAs and alternative splicing regulation during SSC differentiation. Further comparison between young and aged SSCs suggested these differentiation programs were affected by aging. We identified aberrant expression of genes associated with meiosis and TGF-β signaling , alteration in alternative splicing regulation and differential expression of specific lncRNAs such as Fendrr.

2021-06-14 | GSE164604 | GEO

Nanopore-based full-length transcriptome sequencing of yak (Bos grunniens) testis

Project description:Alternative splicing (AS) is strictly regulated during cell differentiation and development. AS events are common in the testis, but the splicing regulation in spermatogenesis is still unclear. In this experiment, the third-generation ONT sequencing was used to sequence the full-length transcriptome of testicular tissue, and 40,038 new transcripts were obtained, and the proportion was almost close to the number of known transcripts identified. A total of 7,645 fused transcripts, 15,355 ASs, 25,798 SSRs, and 35,503 lncRNAs were detected. Through gene co-expression network analysis, the key pathways and Hub genes in each stage of yak testicular development were confirmed. The effects of alternative splicing and splicing variation on mammalian spermatogenesis will provide new insights into the potential application of alternative splicing in the treatment of male infertility.

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