Regulators and Regulation of MHC class II genes

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DESCRIPTION (provided by applicant): Major histocompatibility complex class II gene transcription is tightly regulated, to ensure effective immune system activity. Inappropriate expression of these genes can result in autoimmune disease. Understanding the molecular mechanisms of MHC II transcription may allow the creation of novel immune based therapies for many human diseases. Gene-specific transcription factors assemble at MHC II promoters, to initiate transcription. Of critical importance are the heterotrimeric regulatory factors X (RFX) complex and the class II trans-activator protein (CUTA). CIITA, and one subunit of RFX known as RFXAP, both interact with a chromatin remodeling factor, brahma related gene-1 (BRG1). Whether the RFXAP-BRG1 interaction leads to chromatin remodeling appears to be dependent on cell-type. To explain this observation, it is hypothesized that the appropriate histone modifications must be present at MHC II promoters for RFXAPBRG1 to effectively remodel chromatin. In specific aim 1, histone modifications, and the enzymes responsible for those modifications, will be characterized at MHC II promoters. The observed modifications will be correlated with the ability of RFXAP-BRG1 and CIITA-BRG1 interactions to remodel chromatin. Results will provide insight into cell-type specific regulatory mechanisms controlling MHC II transcription. In the specific aim 2, a new transcriptional regulatory protein for MHC class II genes will be characterized. A cDNA that codes for a novel protein that binds the C-terminus of CIITA was recently cloned. This zinc finger protein is called CCB1. Over-expression of CCB1 results in super-activation of MHC class I and class II genes by CIITA. It is likely that CCB1 binds DNA, and may in fact interact with the W-box of MHC promoters. Employing biochemical and genetic techniques, the manner in which CCB1 alters MHC class II transcription, and CIITA activity, will be addressed. In addition, a broader role for CCB1 in gene regulation, beyond MHC genes, will be explored.