HLA-B locus-specific downregulation in human melanoma requires enhancer A as well as a sequence element located downstream of the transcription initiation site.
Human MHC class I molecules are encoded by three different loci (HLA-A, -B, and -C), which are regulated at the transcriptional level through several conserved cis-acting promoter elements. The presence of locus-specific residues throughout the entire promoter region strongly suggests that the various HLA class I loci are differentially regulated. To identify regulatory sequences involved in locus-specific HLA class I gene transcription, a series of truncated HLA-A2 and HLA-B7 promoter-reporter constructs were transfected into melanoma cell lines expressing high and low levels of endogenous HLA-B, but comparable levels of HLA-A. These experiments showed that differential regulation of HLA-B expression in melanoma cell lines is mediated by a previously unidentified co-operative action of enhancer A, located 175 bp upstream of the transcription initiation site (+1), and a specific region of 20 nucleotides located at +13 to +33 bp downstream of the transcription initiation site. Furthermore, we demonstrated binding of transcription factor Yin Yang 1 to the HLA-A +13/+33 bp region, but not to the equivalent HLA-B region. Based on these results, we present a model suggesting that YY1 displaces either activating or repressing transcription factors, thereby making the HLA-A gene resistant to differential regulation.
Griffioen
M
M
Department of Clinical Oncology, Leiden University Medical Center, The Netherlands.
Ouwerkerk
I J
IJ
Harten
V
V
Schrier
P I
PI
D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004742:Enhancer Elements, Genetic; D050981:Erythroid-Specific DNA-Binding Factors; D015789:HLA-A2 Antigen / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics*; D015793:HLA-B7 Antigen / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000276:immunology; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D050986:YY1 Transcription Factor
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D015789:HLA-A2 Antigen; D015235:HLA-B Antigens; D015793:HLA-B7 Antigen; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human