The appropriate and normal regulation of MHC class II genes is central to a healthy and active immune system and critical for our ability to combat pathogens. The class II transactivator, CIITA, is the master regulator of MHC-II gene expression. Despite extensive analysis of CIITA important aspects of CIITA biology and therefore MHC-II regulation remain unknown. This proposal will focus on three aspects of CIITA structure, regulation, and function. CIITA self-associates, a property that is critical to its function, but how oligomerization contributes to CIITA's ability to activate MHC-II genes is not known.
In Aim 1, we will test the hypothesis that oligomerization contributes to the ability of CIITA to bind to its target proteins on MHC-II promoters, interact and control chromatin remodeling, and/or serve to link regulatory elements.
The second aim seeks to determine the mechanism of CIITA gene silencing that occurs as germinal center B cells differentiate into plasma cells. Our data indicate that gene silencing occurs at the level of the local chromatin structure and is mediated by changes in specific histone modifications. Importantly, a set of global repressers (Blimp-1) and co-repressors (MTA-3 and BCL-6) has been identified that mediate the transition to plasma cells or the maintenance of the B cell program, respectively. Along with cell culture systems, these repressers will be used to ectopically control CIITA silencing and expression such that the molecular mechanism of chromatin control can be elucidated. CIITA will therefore serve as a model for this important cell fate decision. Lastly, in DC and macrophages CIITA is transcribed from the first (pl) of four promoters. This transcript (pl-CIITA) encodes a unique isoform with enhanced transcriptional activity, yet the exact function of this isoform and the specific role of this DC/macrophage specific promoter are unknown.
In Aim 3, we will create mice to examine the novel role that this promoter and its isoform play in developing and initiating immune responses. Because DC/macrophages provide the front line defense to pathogens, this model system will provide a clear role for this promoter and isoform. Thus, the central goal of this application is to understand fully the molecular mechanisms by which CIITA functions to regulate the MHC-II gene system. The results of these studies will ultimately identify targets for immune based therapies for the infectious disease, autoimmune disorders, and organ transplantation.
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