mRNA alternative polyadenylation in B cell development

B 细胞发育中的 mRNA 替代多聚腺苷酸化

• 批准号: 10502155
• 负责人: Roger Sciammas
• 金额: $ 79.4万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-26 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10502155
• 关键词: Alleles; Alternative Splicing; Antibodies; Antibody Response; Autoimmune Diseases; B-Cell Activation; B-Cell Development; B-Lymphocytes; Biochemical; Biochemical Genetics; Biological Process; CRISPR screen; Cell physiology; Cells; Complex; Data; Development; Disease; Gene Expression Regulation; Genes; Immune response; Immunoglobulin M; Individual; Link; Malignant Neoplasms; Membrane; Messenger RNA; Modeling; Neurodegenerative Disorders; Pattern; Play; Polyadenylation; Post-Transcriptional Regulation; Process; Protein Isoforms; Proteins; RNA Processing; RNA-Binding Proteins; Regulation; Reporter; Reporting; Role; Signaling Protein; Testing; Transcript; Transcriptional Activation; Transcriptional Regulation; Work; base; cell mediated immune response; design; gene network; genetic approach; genome-wide; insight; novel; transcription factor; vaccine development

Project summary: The vast majority of mammalian genes produce alternatively processed mRNAs through alternative splicing and alternative polyadenylation (APA). Different mRNA isoforms produced from the same gene can encode distinct proteins and/or they may be differentially regulated. Recent studies have revealed essential roles of mRNA alternative processing in many biological processes and mis-regulation of alternative splicing and APA has been causally linked to a wide range of diseases, including cancer and neurodegenerative diseases. However, the mechanism and functions of alternative mRNA processing remain poorly understood.Antibody secretion by B cells is a major component of our immune response and mis-regulated antibody response underlies many auto-immune diseases. B cell activation and differentiation require a sophisticated gene regulation cascade. Previous works, including ours, have provided insights into the transcriptional regulation mechanisms governing this process. However, it is clear that post- transcriptional gene regulation, such as alternative splicing and APA, also play an important role. In 1980, several landmark studies reported the first example of alternative RNA processing: the Immunoglobulin M (IgM) heavy chain gene (IghM) produces two APA isoforms, which encode a membrane-bound and a secreted IgM respectively. Additionally the IghM APA is developmentally regulated. Subsequent studies, however, have failed to provide a consistent mechanistic model for this APA switch. Furthermore, it remains unknown how widespread the APA regulation network is and what the functional impact of APA regulation is during B cell activation and differentiation. In our preliminary studies, we provided evidence that transcription factors, core mRNA 3’ processing factors, and RNA-binding proteins regulate IghM APA. In addition, we discovered that B cell activation leads to a significantly change in the APA patterns of ~900 genes, including those encoding key cell fate regulators and signaling proteins. Based on these preliminary results, we hypothesize that the APA of IghM and a large gene network are regulated at multiple levels and that APA regulation plays an important role in B cell functions. To test these hypotheses, we have designed the following specific aims: 1) Identify regulators of B cell activation-induced IghM APA switch using a biochemical and genetic approach; 2) Systematically characterize the mechanisms of B cell activation-induced IghM APA switch; 3) Determine the role of APA regulation in B cell activation and differentiation. Successful completion of the proposed studies will provide fundamental insights into APA regulation and function. More importantly, our results will reveal the role of post-transcriptional gene regulation in B cell development and B cell- mediated immune response, which will pave the way for better strategies for developing vaccines and treatment for autoimmune diseases.

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