The proximal regulatory element of the interferon-gamma promoter mediates selective expression in T cells.
Interferon-gamma (IFN-gamma) is produced by natural killer cells and certain subsets of T cells, but the basis for its selective expression is unknown. Within the region between -108 and -40 base pairs of the IFN-gamma promoter are two conserved and essential regulatory elements, which confer activation-specific expression in T cells. This report describes studies indicating that the most proximal of these two regulatory elements is an important determinant of its restricted expression. The proximal element is a composite site that binds members of the CREB/ATF, AP-1, and octamer families of transcription factors. Jun is essential for activation-induced transcription and binds preferably as a heterodimer with ATF-2. In contrast, CREB appears to dampen transcription from this element. The CpG dinucleotide in this element is selectively methylated in Th2 T cells and other cells that do not express IFN-gamma, and methylation markedly reduces transcription factor binding. As a target for DNA methylation and for binding of transcription factors that mediate or impede transcription, this element appears to play a central role in controlling IFN-gamma expression.
Penix
L A
LA
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520-8064, USA. cbwilson@u.washington.edu
Sweetser
M T
MT
Weaver
W M
WM
Hoeffler
J P
JP
Kerppola
T K
TK
Wilson
C B
CB
D051697:Activating Transcription Factor 1; D051698:Activating Transcription Factor 2; D001665:Binding Sites; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D018983:DNA Footprinting; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D017930:Genes, Reporter; D051863:Host Cell Factor C1; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics*; D019169:Jurkat Cells; D016350:Leucine Zippers; D016296:Mutagenesis; D050811:Octamer Transcription Factor-1; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
C497105:ATF2 protein, human; D051697:Activating Transcription Factor 1; D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C497692:HCFC1 protein, human; D051863:Host Cell Factor C1; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D007371:Interferon-gamma; D016572:Cyclosporine