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Role of Zfp318 in the functional development of B cells

Zfp318 在 B 细胞功能发育中的作用

基本信息

批准号：
8990957
负责人：
Janis J. Weis
金额：
$ 18.63万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8990957
关键词：
Address Affinity Alleles Alternative Splicing Androgen Receptor Animals Antibodies Antigens Autoantibodies Autoimmune Responses B-Cell Development B-Lymphocytes Binding Binding Proteins Binding Sites Biological Assay Cell Lineage Cell Maturation Cell physiology Chromatin Code Complex DNA DNA Binding Data Development Drops Event Exons Family member Fever Gene Expression Profile Generations Genes Genetic Enhancer Element Goals Grant Health Heterogeneous Nuclear RNA Human Immune Immune response Immunization Immunoglobulin D Immunoglobulin M Immunologic Deficiency Syndromes Infection Manuscripts Mature B-Lymphocyte Memory B-Lymphocyte Messenger RNA Modification Molecular Molecular Profiling Mus Nuclear Pathway interactions Precipitation Production Proteins RNA RNA Splicing RNA-Binding Proteins Receptor Signaling Recurrence Regulation Research Ribonucleoproteins Role Site Specificity Staging Structure Structure of germinal center of lymph node Syndrome T-Lymphocyte Transcript Transcriptional Activation Transgenic Animals Translations United States National Institutes of Health Vertebrates Zinc Fingers base design gene product gene repression immune activation mRNA Stability novel promoter protein function research study response transcription factor transcription termination

项目摘要

DESCRIPTION (provided by applicant): The primary focus of this revised R21 application is on defining the functions(s) of the zinc finger family member Zfp318 in the development and function of B cells. Previously we demonstrated that Zfp318 is expressed during B cell maturation and shows the highest level of expression in mature, naïve follicular B cells. Zfp318 possesses 2 zinc finger domains as well as nuclear localization motifs: it is in a class of protein with RNA and/or DNA binding potential. We have created a Zfp318 conditional deletion allele and show in data included in this application and a manuscript in press that B cells lacking the protein fail to produce IgD. IgD, in naïve maturing and mature B cells, is coordinately expressed with IgM via alternative splicing of the Ighm/Ighd locus. B cells lacking Zfp318 continue to express VDJ-IgM but lose the ability to generate the VDJ-IgD product. New data generated since the first submission demonstrates that Zfp318 does not function to alter the alternative splicing of the Ighm/Ighd hnRNA, but instead allows for the production of this entire hnRNA by blocking the transcription termination site at the end of the IgM- encoding exons. In the absence of Zfp318, virtually all of the Ighm transcripts terminate prior to the IgD-encoding exons. Amazingly, the Ighm/Ighd gene is the only locus in B cells that shows such altered expression profiles which means that Zfp318 has evolved to singularly control this event. The experimental plan of this application section is focused upon accomplishing three specific goals. First, we will determine if there are functional consequences to the B cell and the immune response created by the absence of Zfp318. IgD and Zfp318 have co-evolved since the development of primitive vertebrates, our Zfp318 deficient animal will provide us a unique vantage to ascertain the importance of these proteins to the immune response. Secondly we will address how Zfp318 functions. Does it bind to DNA, does it bind to RNA? The fact Zfp318 only modulates Ighm/Ighd expression indicates the protein possesses a very high level of sequence/structure specificity. And finally we will address how the regulation of the expression of the Zfp318 gene is integrated into B cell development and activation. We know from our previous studies that the expression of Zfp318 is dramatically influenced by Mef2c, a transcription factor known to modulate B cell development and activation. How Zfp318 fits into this network of expression and function is the primary goal of this last question.