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The RNA binding protein Bcas2 is necessary for antibody class switch in mammalian genomes

ABSTRACT: In children, hyper-IgM syndrome type 1 (HIGM1) is a type of severe antibody disorder, the pathogenesis of which remains unclear. Here we report for the first time that breast cancer amplified sequence 2 (BCAS2), known as an RNA-binding protein, regulates the antibody class transition processes through alternative splicing (AS). Based on integrated analysis of the whole genome sequence and CLIP-seq data, we revealed that BCAS2 regulates AS through binding to the GAAGAA motif of target genes in B cells. Besides, BCAS2 can interact with SRSF7/DHX15 proteins and form spliceosomes that regulates AS and mRNA levels of target genes. In HIGM2 patients, BCAS2 affected the AS and expression of key target genes, and consequently the serum antibody levels. Collectively, the results in this study show that Bcas2 forms a complex with factors such as SRSF7 to regulate AS of key genes, thereby affecting the antibody production. The deletion or reduced expression of BCAS2 may lead to the HIGM2 phenotype. The present study reveals for the first time the pathogenesis of HIGM2, providing a potential molecular target for treatment of the disease.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE271398 | GEO | 2025/07/02

REPOSITORIES: GEO

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BCAS2 regulates granulosa cell survival via participating in Flt3l mRNA splicing

Project description: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.

2023-06-01 | GSE218919 | GEO

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

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BCAS2 promotes primitive hematopoiesis by sequestering β-catenin within the nucleus

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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.

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

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