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

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. Overall design: BCAS2 CLIP-seq was performed with naïve spenic B cells and LPS-activated B cells, and two biological replications were labeled as Rep1 and Rep2 respectively. Two biological repeats of mouse IgG CLIP-seq in LPS-activated B cells were labeled as Rep1 and Rep2. Meantime, BCAS2 RNA-seq was performed with or without the depletion of BCAS2 in activated B cells. The RNA-seq of peripheral blood mononuclear cells from two healthy person and HIGM1 patients was also performed. Two biological replications were labeled as Rep1 and Rep2 respectively.