REGULATION OF EXPRESSION OF MHC CLASS I GENES

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Regulation of MHC class I gene transcription is mediated by the coordinate activities of the basal promoter and upstream regulatory elements, to achieve tissue-specific levels of expression which are further dynamically modulated in response to extracellular signals. The recent research focus of the laboratory has been to define the critical sequence organization of the basal promoter, the transcription initiation complexes that are required for transcription of the basal promoter, and upstream elements that modulate basal promoter activity. The class I basal promoter consists of three elements: a TATAA box, an initiator (Inr), and a novel S-box element. The relative usage of TATAA and Inr elements varies among different cell types, but neither element is absolutely required in any cell type tested. Two sites, 3 of the TATAA box and 5 of the Inr, do appear to be necessary for basal promoter activity. The function of these elements in vivo is being examined in a series of transgenic mouse constructs. Transcription of the basal class I promoter -whether through the TATAA or Inr elements - depends on a functional TAFII250, a component of the TFIID complex. Furthermore, we have demonstrated that the HIV Tat protein binds to TAFII250, inhibiting its HAT activity and repressing class I transcription. Using a yeast two-hybrid system, we have identified a series of novel cellular proteins that similarly interact with TAFII250. We speculate that these factors contribute to the normal cellular regulation of class I transcription; their functions are under investigation. Dependence on TAFII250 can be overcome by strong upstream enhancer elements and transcription factors. This observation has led us to propose that the nature of the transcription initiation complex can be modulated by tissue-specific and dynamically controlled transcription factors. In support of this hypothesis, we find that cell type specific enhanceosomes contribute to the regulation of class I transcription. In particular, the interferon inducible regulator of MHC class II expression, CIITA, is a potent co-activator of class I expression. Coactivation by CIITA requires both the interferon response element and the CRE; in contrast, neither CBP, PCAF nor p300 affect class I transcription.A variety of upstream elements contribute to the regulation of MHC class I genes. Tissue specific expression of class I genes is determined by a series of upstream regulatory elements. A distal E box element acts as a cell type-specific enhancer: it is active in a neuroblastoma line but relatively inactive in the HeLa epithelial cell line. The bZIP transcription factors, USF1 and USF2, bind and activate class I transcription. In contrast, whereas the naturally occurring variant, USF2dE4 is a dominant negative regulator of class I transcription. The relative levels of the variant determine the level of USF activation of the class I promoter, leading to the proposal that this may represent one mechanism to fine-tune class I expression in various tissues.