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BCAS2 regulates granulosa cell survival via participating in Flt3l mRNA splicing

ABSTRACT: Granulosa cell proliferation and differentiation are essential for follicle development. Breast cancer amplified sequence 2 (BCAS2) is necessary for spermatogenesis, oocyte development, and maintaining the genome integrity of early embryos in mice. However, the function of BCAS2 in granulosa cells is still unknown. We show that conditional disruption of BCAS2 causes follicles development failure; cell proliferation markers PCNA and Ki67 positive cell ratio are unchanged in granulosa cells. However, specific deletion of BCAS2 causes BrdU positive cell ratio to decrease, cell cycle arrest appearance, DNA damage, and cell apoptosis increase in granulosa cells, RPA1 was abnormally stained in granulosa cells. Furthermore, RNA-Seq results reveal that knockout of BCAS2 results in cellular senescence gene unusual expression. BCAS2 participates in the PRP19 complex to mediate alternative splicing (AS) of E2f3 and Flt3l mRNA to inhibit the cell cycle. Knock down of BCAS2 results in a significantly decrease of BrdU positive cell ratio in Human granulosa-like tumor(KGN) cell line. Thus, BCAS2 regulates granulosa cell proliferation, DNA damage repair, and cell apoptosis. BCAS2 is vital for female fertility.

ORGANISM(S): Mus musculus

PROVIDER: GSE218919 | GEO | 2023/06/01

REPOSITORIES: GEO

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BCAS2 regulates oocyte meiosis by participating in alternative mRNA splicing

Project description:Oocyte meiosis is an important factor affecting female reproduction. Breast cancer amplified sequence 2 (BCAS2) is a component of the spliceosome. Previous reports have shown that BCAS2 is critical in male germ cell meiosis, oocyte development, and early embryo genome integrity. However, the role of BCAS2 in oocyte meiosis has not been reported. We used Stra8-GFP-Cre mice to knock out BCAS2 during the pachytene phase of oocytes. The results of fertility tests showed that the cko mice were infertile. Morphological analysis showed that the number of primary follicles of 2M ovary was significantly reduced and follicle development was blocked. Further analysis showed that the number of primordial follicles decreased and follicle development slowed from 7dpp ovaries. Sequencing revealed that DNA damage in oocytes could not be repaired from 5dpp. There was an abnormality in meiosis, some oocytes could not reach the diplotene stage of meiosis, and more oocytes could not develop to the dictyate stage. AS analysis reveals that abnormal variable splicing of Dazl and Diaph2 Oogens-related genes in cKO mice, with involvement of the PRP19/CDC5l complex.

2024-01-01 | GSE228983 | GEO

BCAS2 regulates granulosa cell survival via participating in Flt3l mRNA splicing

Project description:BCAS2 regulates granulosa cell survival via participating in Flt3l mRNA splicing

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BCAS2 regulates oocyte meiosis by participating in alternative mRNA splicing

Project description:BCAS2 regulates oocyte meiosis by participating in alternative mRNA splicing

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BCAS2 is involved in insulin synthesis and secretion by mRNA alternative splicing

Project description:Insulin secreted by pancreatic β cells is essential for maintaining the level of blood glucose. Diabetes is mainly caused by the loss of β cells or impaired β cell function. The previous study performed a whole transcriptome analysis on the islets of T2D and the control group, and the results showed that the splicing disorder of the splicing event was about 25%, breast carcinoma amplified sequence 2(BCAS2) is one of the components of the spliceosome, and its function in islet β cell is unclear. Here we report that knockdown of Bcas2 decreases in glucose and KCl-stimulated insulin secretion in the NIT-1 cell line. The pancreas weight, glucose tolerance and insulin sensitivity were detected in normal chow-fed and high-fat diet-fed Bcas2 f/f-βKO mice, and β cell mass and islet size was analyzed by immunohistochemistry. Glucose intolerance developed in Bcas2 f/f-βKO mice, but there were no significant differences in pancreas weight, insulin sensitivity, β cell mass and islet size. Further, GSIS and observation of insulin secretion granules were performed on normal chow-fed mice, and it was found that the insulin level in serum decreased and the number of insulin secretion granules decreased in Bcas2 f/f-βKO mice, which was related to the abnormal splicing of Syt7 and Tcf7l2 pre-mRNA. Taken together, these results demonstrate that BCAS2 is involved in alternative splicing during insulin synthesis and secretion. Elisa,islet isolation,insulin secretion

2024-06-01 | GSE224490 | GEO

BCAS2 is involved in alternative mRNA splicing in spermatogonia and the transition to meiosis and male fertility

Project description:BCAS2 (Breast cancer amplified sequence 2) is involved in multiple biological processes, including pre-mRNA splicing. However, the physiological roles of BCAS2 are still largely unclear. Here we report that BCAS2 is specifically enriched in spermatogonia of mouse testes. Conditional disruption of Bcas2 in male germ cells impairs spermatogenesis and leads to male mouse infertility. Although the spermatogonia appear grossly normal, spermatocytes in meiosis prophase I and meiosis events (recombination and synapsis) are rarely observed in the BCAS2-depleted testis. In BCAS2 null testis, 245 genes are altered in alternative splicing forms; at least three spermatogenesis-related genes (Dazl, Ehmt2 and Hmga1) can be verified. In addition, disruption of Bcas2 results in a significant decrease of the full-length form and an increase of the short form (lacking exon 8) of DAZL protein. Altogether, our results suggest that BCAS2 regulates alternative splicing in spermatogonia and the transition to meiosis initiation, and male fertility.

2016-11-15 | GSE89801 | GEO

RNA-seq analysis of the WT and bcas2-KO zebrafish embryos at 3 dpf

Project description:The splicing factor Bcas2 is involved in several biological processes including tumorigenesis, gametogenesis, and hematopoiesis. The alternative splicing events and downstream genes regulated by Bcas2 have not yet been investigated at the transcriptome level in zebrafish. In this study, we conducted RNA-sequencing analysis on the WT and bcas2 knockout zebrafish embryos (3 dpf) to identify the global differentially expressed genes (DEGs) and differential splicing events (DSEs). 868 DEGs (293 up and 575 down) were identified and genes related to spliceosome, mRNA splicing, and mRNA processing were significantly upregulated, suggesting a negative feedback of the splicing pathway. Besides, 664 DSEs related to 593 genes were identified and sequence signature analysis of these DSEs revealed that the alternatively spliced exons affected by bcas2 knockout have relatively shorter length, longer upstream and downstream introns, and weaker 5’ or 3’ splicing sites, when compared with the control exons. Furthermore, we demonstrated that the exon 5 of ikzf1 gene, a transcription factor related to lymphocyte differentiation, was preferably skipped in the bcas2 knockout embryos, resulting in the deletion of 11 aa between the two conserved zinc finger domains of Ikzf1. Accordingly, several downstream genes, such as rasgrp2 and rgs2, were significantly downregulated and the lymphocyte generation was impaired in the bcas2 knockout embryos. Taken together, our work depicts the global changes of gene expression and alternative splicing caused by bcas2 knockout in zebrafish embryos and reveals an important role of Bcas2-regulated alternative splicing of ikzf1 in lymphoid hematopoiesis.

2024-06-01 | GSE246374 | GEO

miRNA expression data in MCF-7 breast cancer Cell line post BCAS2 and FST knockdown

Project description:Previously, we have confirmed the tumor suppressive role of Estrogen Related Receptor β (ERRβ) in breast cancer by modulation of ER transcriptional activities on Breast Cancer Amplified Sequence 2 (BCAS2) and Follistatin(FST).In the mentioned study, we proved downregulation of Cyclin D1 by BCAS2.In the previous report, we have also proved downregulation of FST by BCAS2 through inhibition of β-catenin/TCF-4 complex recruitment on FST promoter. Interestingly, Cyclin D1 induction by FST has been also reported by a different group.Recently, Cyclin D1 expression has been found to be associated with DICER1 induction. Hence it may be speculated, that a part of miRNA population, which involves Dicer for processing, is regulated by BCAS2. And it is also possible, that FST may oppose the effect of BCAS2 on those Dicer-processed miRNAs.This Dicer-regulation by Cyclin D1was reported in Luminal A type of breast cancer. Hence, we chose MCF-7 breast cancer cells for miRNA profiling post knocking down BCAS2 and FST.

2017-10-31 | GSE89390 | GEO

BCAS2 and hnRNPH1 orchestrate alternative splicing for DNA double-strand break repair and synapsis in meiotic prophase I [RNAs-seq]

Project description:Understanding the intricacies of homologous recombination during meiosis is crucial for reproductive biology. However, the role of alternative splicing (AS) in DNA double-strand breaks (DSBs) repair and synapsis remains elusive. In this study, we investigated the impact of conditional knockout (cKO) of the splicing factor gene Bcas2 in mouse germ cells, revealing impaired DSBs repair and synapsis, resulting in non-obstructive azoospermia (NOA). Employing crosslinking immunoprecipitation and sequencing (CLIP-seq), we globally mapped BCAS2 binding sites in the testis, uncovering its predominant association with 5' splice sites (5'SS) of introns and a preference for GA-rich regions. Integrating CLIP-seq with RNA-seq, we identified BCAS2 as a key player in the AS of pre-mRNAs, including Spo11, Six6os1, Sycp1, Msh5, Cdk2, Sun2, Stag3, and Spdya, crucial for DSBs repair and synapsis. Notably, BCAS2 exhibited direct binding and regulatory influence on Trp53bp1 and Six6os1 through AS, unveiling novel insights into DSBs repair and synapsis during meiotic prophase I. Furthermore, the interaction between BCAS2, hnRNPH1, and SRSF3 was discovered to orchestrate Trp53bp1 expression via AS, underscoring its role in meiotic prophase I DSBs repair. In summary, our findings delineate the indispensable role of BCAS2-mediated post-transcriptional regulation in DSBs repair and synapsis during male meiosis. This study provides a comprehensive framework for unraveling the molecular mechanisms governing the post-transcriptional network in male meiosis, contributing to the broader understanding of reproductive biology.

2024-03-25 | GSE254463 | GEO

BCAS2 and hnRNPH1 orchestrate alternative splicing for DNA double-strand break repair and synapsis in meiotic prophase I [CLIP-seq]

2024-03-25 | GSE254462 | GEO

BCAS2 regulates granulosa cell survival by participating in mRNA alternative splicing.

Project description:BackgroundGranulosa cell proliferation and differentiation are essential for follicle development. Breast cancer amplified sequence 2 (BCAS2) is necessary for spermatogenesis, oocyte development, and maintaining the genome integrity of early embryos in mice. However, the function of BCAS2 in granulosa cells is still unknown.ResultsWe show that conditional disruption of Bcas2 in granulosa cells caused follicle development failure; the ratio of the positive cells of the cell proliferation markers PCNA and Ki67 were unchanged in granulosa cells. Specific deletion of Bcas2 caused a decrease in the BrdU-positive cell ratio, cell cycle arrest, DNA damage, and an increase in apoptosis in granulosa cells, and RPA1 was abnormally stained in granulosa cells. RNA-seq results revealed that knockout of Bcas2 results in unusual expression of cellular senescence genes. BCAS2 participated in the PRP19 complex to mediate alternative splicing (AS) of E2f3 and Flt3l mRNA to inhibit the cell cycle. Knockout of Bcas2 resulted in a significant decrease in the ratio of BrdU-positive cells in the human granulosa-like tumour (KGN) cell line.ConclusionsOur results suggest that BCAS2 may influence the proliferation and survival of granulosa cells through regulating pre-mRNA splicing of E2f3 and Flt3l by forming the splicing complex with CDC5L and PRP19.

| S-EPMC10226250 | biostudies-literature

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