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  • Title: A 150-base pair 5' region of the MHC class I HLA-B7 gene is sufficient to direct tissue-specific expression and locus control region activity: the alpha site determines efficient expression and in vivo occupancy at multiple cis-active sites throughout this region.
    Author: Kushida MM, Dey A, Zhang XL, Campbell J, Heeney M, Carlyle J, Ganguly S, Ozato K, Vasavada H, Chamberlain JW.
    Journal: J Immunol; 1997 Nov 15; 159(10):4913-29. PubMed ID: 9366417.
    Abstract:
    To characterize cis- and trans-acting mechanisms that regulate MHC class I transcription during development and in adult tissues, we have used transgenic mice to study a series of human MHC (HLA)-B7 class I gene constructs. Previous studies identified the 5' -0.66-kb to -0.075-kb region as sufficient to direct appropriate and efficient tissue-specific levels of HLA-B7 RNA relative to H-2 class I. Results here show that DNA 5' of -0.26 kb is not required for any aspect of expression. As the expression level correlated with the transgene copy number, was comparable to H-2 or a per-gene copy basis and was independent of integration site, the -0.075 to -0.26-kb segment also functions as a locus control region. With this region, sequences 3' of -0.075 kb, possibly at the promoter, appear to direct the appropriate tissue distribution. Of conserved sequences in the -0.075 to -0.26-kb region, enhancer B box is nonessential. In contrast, in vivo "footprinting" implicated region I/ enhancer A/NF-kappaB, IFN consensus/response sequence, and alpha in class I regulation as they are "occupied" in a tissue-specific pattern that correlates with expression. Mutation of alpha leads to decreased expression and loss of occupancy not only at alpha but also at region I/enhancer A/NF-kappaB and IFN consensus/response sequence. Thus, site alpha is an essential class I regulatory element, the dominant function of which is to mediate tissue-specific occupancy at multiple adjacent cis-active sites, possibly by facilitating stable synergistic interactions between factors at these distinct elements.
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