MHC class I genes encoding transplantation antigens are ubiquitously expressed, although their level of expression varies among tissues. Analysis of the 5' flanking DNA sequence of a swine class I gene has demonstrated that in addition to the canonical promoter, this region contains a series of negative and positive regulatory element. One of these elements, consisting of overlapping negative and positive regulatory elements, constitutes 'a regulatory domain responsible for establishing homeostatic, tissue-specific levels of MHC class I gene expression. Introduction into transgenic mice of a series of nested deletion mutants which differ in the extent of the regulatory domain, reveals that the enhancer activity predominates in lymphoid tissues, but not in lymphoid tissues. The tissue-specific domain forms distinct enhancer and silencer associated complexes with cellular trans acting factors. Analysis of binding activity from a variety of cell lines and tissues reveals that enhancer binding activity is present in all extracts, independent of levels of class I expression. In contrast, the level of silencer binding activity is inversely proportional to the level of class I gene expression. These studies have led to the proposal that class I genes are negatively regulated. Biochemical characterization of the regulatory factors has demonstrated that each factor consists of at least two distinct components, one of which appears to be common to both factors. Both the silencer and enhancer factors are redox-sensitive. The enhancer factor complex is approximately 30 kD; the silencer factor complex is approximately 95 kD. A negative regulatory element has been identified which functions in transgenic animals in all tissues examined. Removal of this element results in markedly elevated levels of class I expression, both in transient transfection assays and in transgenic mice. Characterization of this element reveals that it is a TRE-like element. Indeed, c-jun, which binds to this element, acts as a specific negative regulator of MHC class I expression.
