Essential role of transcription factor Foxp1 in B cell development and function

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DESCRIPTION (provided by applicant): The long-term objective of this application is to understand the transcriptiorial control of cell development and functional regulation in immune system. Recently a novel transcription factor, Foxp1, has been identified as an essential regulator in B lymphopoiesis with mechanism(s) largely unknown. In this application, three specific aims are proposed: 1) to elucidate the mechanism(s) underlying the regulation of Foxp1 expression in B lymphopoiesis; 2) to elucidate the molecular mechanism(s) by which Foxp1 engages in transcriptional control of early B cell development; 3) to determine the functions of Foxp1 in mature B cells. The successful generation of competent B lymphocytes is vital for effective immune responses. The antibodies produced by B cells are often the first effective defense line against many infectious diseases. The failure or inappropriate differentiation of B cells in B lymphopoiesis would lead to various diseases such as immunodeficiencies, autoimmune diseases and B lymphoid malignancies. The research carried out in this application will help provide important therapeutic value to cure various immune-mediated diseases. In this application, long-range chromatin structure analysis will be employed to understand how Foxp1 expression is regulated. BAC-based gene targeting will be used to study the function of regulatory elements. A protein biotinylation-based ChlP-cloning method will be developed to identify Foxp1 target genes in a genome-wide screening. Mice with conditionally targeted Foxp1 will be generated to study the functions of Foxp1 in mature B cells. The successful generation of competent lymphocytes is vital for effective immune responses against various infectious diseases, while the failure or inappropriate differentiation of such cells would lead to diseases such as immunodeficiencies, autoimmune diseases and lymphoid malignancies. The research on the understanding of lymphocyte development and functional regulation will help provide important therapeutic value to cure various immune-mediated diseases.