REGULATION OF EXPRESSION OF CLASS I MHC GENE

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The aim of this work is to investigate the mechanisms controlling the expression of a multi-gene family. The miniature swine has been chosen as an experimental model because there are only 7 members of the family. To address the question of the molecular regulation of the expression of class I MHC genes, two approaches have been taken: 1) the analysis of in vivo patterns of expression of each of the genes, both in situ and in transgenic mice; and 2) characterization of regulatory elements associated with these genes. Analysis of in vivo patterns reveals that both shared and discrete regulatory mechanisms operate within the family. Thus, some genes are coordinately expressed, whereas others are not. In both cases, patterns of expression are actively regulated. Regulatory sequences within one of the transplantation antigen genes have been identified by generating a series of 5' end deletion mutants. A series of both positive and negative elements have been mapped. A novel negative regulatory element, which requires the presence of a positive element in order to function, has been identified. It has been further demonstrated that these elements function through the binding of tran sacting factors. The binding sites of the trans acting factors have been mapped using both gel retardation assays and exonuclease protection.