The RNA Binding Protein Bcas2 is Required for Antibody Class Switch in Activated‐B Cells
ABSTRACT In children, hyper‐IgM syndrome type 1 (HIGM1) is a type of severe antibody disorder, the pathogenesis of which remains unclear. The antibody diversity is partially determined by the alternative splicing (AS) in the germline, which is mainly regulated by RNA‐binding proteins, including Brea...
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Wiley
2025-06-01
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| Online Access: | https://doi.org/10.1002/EXP.70015 |
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| author | Yu Chen Siyuan Sun Chenxu Lu Yixuan Li Bing Fang Xiangfeng Tang Xuepeng Li Weiru Yu Yumei Lei Longjie Sun Ming Zhang Jiazeng Sun Ping Liu Yongting Luo Xingwang Zhao Jing Zhan Libing Liu Rong Liu Jiaqiang Huang Ziwei Yi Yifei Yu Weihan Xiao Zheng Ding Lei Li Dan Su Fazheng Ren Changchang Cao Ran Wang Wenbiao Shi Juan Chen |
| author_facet | Yu Chen Siyuan Sun Chenxu Lu Yixuan Li Bing Fang Xiangfeng Tang Xuepeng Li Weiru Yu Yumei Lei Longjie Sun Ming Zhang Jiazeng Sun Ping Liu Yongting Luo Xingwang Zhao Jing Zhan Libing Liu Rong Liu Jiaqiang Huang Ziwei Yi Yifei Yu Weihan Xiao Zheng Ding Lei Li Dan Su Fazheng Ren Changchang Cao Ran Wang Wenbiao Shi Juan Chen |
| author_sort | Yu Chen |
| collection | DOAJ |
| description | ABSTRACT In children, hyper‐IgM syndrome type 1 (HIGM1) is a type of severe antibody disorder, the pathogenesis of which remains unclear. The antibody diversity is partially determined by the alternative splicing (AS) in the germline, which is mainly regulated by RNA‐binding proteins, including Breast cancer amplified sequence 2 (Bcas2). However, the effect of Bcas2 on AS and antibody production in activated B cells, the main immune cell type in the germline, remains unknown. To fill this gap, we created a conditional knockout (cKO, B cell‐specific AID‐Cre Bcas2fl/fl) mouse model and performed integrated mechanistic analysis on alternative splicing (AS) and CSR in B cells through the RNA‐sequencing approach, cross‐linking immunoprecipitation and sequencing (CLIP‐seq) analysis, and interactome proteomics. The results demonstrate that Bcas2‐cKO significantly decreased CSR in activated B cells without inhibiting the B cell development. Mechanistically, Bcas2 interacts with SRSF7 at a conservative circular domain, forming a complex to regulate the AS of genes involved in the post‐switch transcription, thereby causing broad‐spectrum changes in antibody production. Importantly, we identified GAAGAA as the binding motif of Bcas2 to RNAs and revealed its essential role in the regulation of Bcas2‐dependent AS and CSR. In addition, we detected a mutation of at the 3’UTR of Bcas2 gene in children with HIGM1 and observed similar patterns of AS events and CSR in the patient that were discovered in the Bcas2‐cKO B cells. Combined, our study elucidates the mechanism by which Bcas2‐mediated AS affects CSR, offering potential insights into the clinical implications of Bcas2 in HIGM1. |
| format | Article |
| id | doaj-art-5108698cedd64a74b8a2b56495dfd88c |
| institution | OA Journals |
| issn | 2766-8509 2766-2098 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Exploration |
| spelling | doaj-art-5108698cedd64a74b8a2b56495dfd88c2025-08-20T02:36:23ZengWileyExploration2766-85092766-20982025-06-0153n/an/a10.1002/EXP.70015The RNA Binding Protein Bcas2 is Required for Antibody Class Switch in Activated‐B CellsYu Chen0Siyuan Sun1Chenxu Lu2Yixuan Li3Bing Fang4Xiangfeng Tang5Xuepeng Li6Weiru Yu7Yumei Lei8Longjie Sun9Ming Zhang10Jiazeng Sun11Ping Liu12Yongting Luo13Xingwang Zhao14Jing Zhan15Libing Liu16Rong Liu17Jiaqiang Huang18Ziwei Yi19Yifei Yu20Weihan Xiao21Zheng Ding22Lei Li23Dan Su24Fazheng Ren25Changchang Cao26Ran Wang27Wenbiao Shi28Juan Chen29Key Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaNational Engineering Laboratory for Birth Defects Prevention and Control of Key Technology Beijing Key Laboratory of Pediatric Organ Failure Department of Pediatrics The Seventh Medical Center of PLA General Hospital Beijing ChinaCollege of Food Science and Engineering Bohai University Liaoning ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaState Key Laboratory of Animal Biotech Breeding College of Biological Sciences China Agricultural University Beijing ChinaSchool of Food and Health Beijing Technology and Business University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaState Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing ChinaDepartment of Chemistry and Chemical Biology Cornell University Ithaca New York USAKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaState Key Laboratory of Cardiovascular Disease Fuwai Hospital National Center for Cardiovascular Diseases Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaKey Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing ChinaABSTRACT In children, hyper‐IgM syndrome type 1 (HIGM1) is a type of severe antibody disorder, the pathogenesis of which remains unclear. The antibody diversity is partially determined by the alternative splicing (AS) in the germline, which is mainly regulated by RNA‐binding proteins, including Breast cancer amplified sequence 2 (Bcas2). However, the effect of Bcas2 on AS and antibody production in activated B cells, the main immune cell type in the germline, remains unknown. To fill this gap, we created a conditional knockout (cKO, B cell‐specific AID‐Cre Bcas2fl/fl) mouse model and performed integrated mechanistic analysis on alternative splicing (AS) and CSR in B cells through the RNA‐sequencing approach, cross‐linking immunoprecipitation and sequencing (CLIP‐seq) analysis, and interactome proteomics. The results demonstrate that Bcas2‐cKO significantly decreased CSR in activated B cells without inhibiting the B cell development. Mechanistically, Bcas2 interacts with SRSF7 at a conservative circular domain, forming a complex to regulate the AS of genes involved in the post‐switch transcription, thereby causing broad‐spectrum changes in antibody production. Importantly, we identified GAAGAA as the binding motif of Bcas2 to RNAs and revealed its essential role in the regulation of Bcas2‐dependent AS and CSR. In addition, we detected a mutation of at the 3’UTR of Bcas2 gene in children with HIGM1 and observed similar patterns of AS events and CSR in the patient that were discovered in the Bcas2‐cKO B cells. Combined, our study elucidates the mechanism by which Bcas2‐mediated AS affects CSR, offering potential insights into the clinical implications of Bcas2 in HIGM1.https://doi.org/10.1002/EXP.70015alternative splicingBcas2class switch recombinationCLIP‐seqhyper‐IgM syndrome type 1RNA binding proteins |
| spellingShingle | Yu Chen Siyuan Sun Chenxu Lu Yixuan Li Bing Fang Xiangfeng Tang Xuepeng Li Weiru Yu Yumei Lei Longjie Sun Ming Zhang Jiazeng Sun Ping Liu Yongting Luo Xingwang Zhao Jing Zhan Libing Liu Rong Liu Jiaqiang Huang Ziwei Yi Yifei Yu Weihan Xiao Zheng Ding Lei Li Dan Su Fazheng Ren Changchang Cao Ran Wang Wenbiao Shi Juan Chen The RNA Binding Protein Bcas2 is Required for Antibody Class Switch in Activated‐B Cells Exploration alternative splicing Bcas2 class switch recombination CLIP‐seq hyper‐IgM syndrome type 1 RNA binding proteins |
| title | The RNA Binding Protein Bcas2 is Required for Antibody Class Switch in Activated‐B Cells |
| title_full | The RNA Binding Protein Bcas2 is Required for Antibody Class Switch in Activated‐B Cells |
| title_fullStr | The RNA Binding Protein Bcas2 is Required for Antibody Class Switch in Activated‐B Cells |
| title_full_unstemmed | The RNA Binding Protein Bcas2 is Required for Antibody Class Switch in Activated‐B Cells |
| title_short | The RNA Binding Protein Bcas2 is Required for Antibody Class Switch in Activated‐B Cells |
| title_sort | rna binding protein bcas2 is required for antibody class switch in activated b cells |
| topic | alternative splicing Bcas2 class switch recombination CLIP‐seq hyper‐IgM syndrome type 1 RNA binding proteins |
| url | https://doi.org/10.1002/EXP.70015 |
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