Transcriptional regulators play pivotal roles in fundamental physiological processes including cell proliferation, differentiation and development. A main interest of my lab is to understand the biology and mechanism of action of Yin Yang 1 (YY1), a zinc finger-containing transcription factor. Studies of YY1 in the past 15 years have provided considerable understanding of the mechanisms by which YY1 regulates transcription, but the physiological roles of YY1 in living organisms are still poorly understood. In the past funding period, we developed a YY1 conditional knockout mouse model and identified crucial roles for YY1 in multiple stages of B cell development. Loss of YY1 results in reduced peripheral mature B cells and an absence of germinal center B cells, suggesting that YY1 is critical for both the maintenance and the antibody production function of B cells. Abnormal B cell proliferation and differentiation are the main causes for B cell lymphoma and leukemia. Rituximab (chimeric anti-CD20 monoclonal antibody) is the first FDA approved antitumor antibody for the treatment of B-non-Hodgkin's lymphoma (B-NHL). Importantly, recent studies suggest that Rituximab treatment inhibits the anti-apoptotic process in B lymphoma cells by down-regulating YY1. Therefore, understanding the molecular mechanism of YY1-mediated B cell development and function in mature B cells will provide clues to the diagnosis and treatment of malignant B cell diseases. We will investigate the molecular mechanism of YY1 in peripheral mature B cells by identifying its potential target genes using whole-genome wide microarray analysis and ChIP-sequencing. We will also investigate the mechanism of YY1-mediated gene transcription by analyzing YY1-mediated chromatin changes and YY1-interacting partners in mature B cells. Taken together, findings from the proposed experiments will provide new insights into B cell development and function as well as developing new methods for the diagnosis and treatment of B cell diseases such as allergy, pathogen resistance, autoimmune diseases and B cell lymphoma and leukemia.
Immunoglobulin gene recombination and maintenance of mature B cells are critical for the generation of almost infinite diversity of antibodies and immune response, respectively. This application proposes to understand mechanisms by which Yin Yang 1 regulates recombination of the immunoglobulin heavy chain locus, and peripheral mature B cell maintenance. Findings from the proposed experiments will not only provide insight into YY1 but also shed new light on B cell development.
