Analysis of regulatory elements in the HLA-A, HLA-B, and HLA-C genes provides insights into the specific role of each HLA in the immune system

Abstract We have conducted a detailed analysis of regulatory elements present in the upstream region of the HLA-A, HLA-B, and HLA-C genes. Significant differences in transcription factor-binding sites were identified in a tissue-specific promoter located 1.3 kb upstream, an enhancer element at −800 bp, and the core promoter region, that alter both the tissue specificity and expression level of the HLA genes. The upstream promoter has changed from macrophage-specificity in HLA-A to an unknown specificity in HLA-B, and it has gained NK specificity in HLA-C that is coupled with an elaborate post-transcriptional regulatory mechanism. The −800 enhancer region contains distinct arrays of transcription factor-binding sites in the HLA-A, HLA-B, and HLA-C genes. A comparison of the proximal promoter region of these three genes revealed multiple differences in key enhanceosome and cytokine-inducible elements, and the presence of additional trophoblast-specific elements in the HLA-C promoter. Furthermore, a comparison of HLA-C alleles reveals functional differences in transcription factor-binding sites that likely reflects allele-specific tuning of expression. A more complete understanding of the molecular evolution of regulatory elements between the HLA-A, HLA-B, and HLA-C genes will provide important clues with regard to the separate immunological functions of the three MHC class I genes present in humans.