title: A GATA factor mediates cell type-restricted induction of HLA-E gene transcription by gamma interferon.
abstract: The human major histocompatibility complex (MHC) class Ib gene, HLA-E, codes for the major ligand of the inhibitory receptor NK-G-2A, which is present on most natural killer (NK) cells and some CD8(+) cytotoxic T lymphocytes. We have previously shown that gamma interferon (IFN-gamma) induction of HLA-E gene transcription is mediated through a distinct IFN-gamma-responsive element, the IFN response region (IRR), in all cell types studied. We have now identified and characterized a cell type-restricted enhancer of IFN-gamma-mediated induction of HLA-E gene transcription, designated the upstream interferon response region (UIRR), which is located immediately upstream of the IRR. The UIRR mediates a three- to eightfold enhancement of IFN-gamma induction of HLA-E transcription in some cell lines but not in others, and it functions only in the presence of an adjacent IRR. The UIRR contains a variant GATA binding site (AGATAC) that is critical to both IFN-gamma responsiveness and to the formation of a specific binding complex containing GATA-1 in K562 cell nuclear extracts. The binding of GATA-1 to this site in response to IFN-gamma was confirmed in vivo in a chromatin immunoprecipitation assay. Forced expression of GATA-1 in nonexpressing U937 cells resulted in a four- to fivefold enhancement of the IFN-gamma response from HLA-E promoter constructs containing a wild-type but not a GATA-1 mutant UIRR sequence and increased the IFN-gamma response of the endogenous HLA-E gene. Knockdown of GATA-1 expression in K562 cells resulted in a approximately 4-fold decrease in the IFN-gamma response of the endogenous HLA-E gene, consistent with loss of the increase in IFN-gamma response of HLA-E promoter-driven constructs containing the UIRR in wild-type K562 cells. Coexpression of wild-type and mutant adenovirus E1a proteins that sequester p300/CBP eliminated IFN-gamma-mediated enhancement through the UIRR, but only partially reduced induction through the IRR, implicating p300/CBP binding to Stat-1alpha at the IRR in the recruitment of GATA-1 to mediate the cooperation between the UIRR and IRR. We propose that the GATA-1 transcription factor represents a cell type-restricted mediator of IFN-gamma induction of the HLA-E gene.
authors.affiliation: Massey Cancer Center, Department of Human Genetics, Virginia Commonwealth University, Richmond, VA 23298-0037, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Barrett
authors.forename: Karen S
authors.initials: KS
authors.lastname: Gustafson
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Shou Zhen
authors.initials: SZ
authors.lastname: Wang
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Ginder
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006680:HLA Antigens / Q000235:genetics* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D000097625:HLA-E Antigens
chemical_list: D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma; D014157:Transcription Factors; D000097625:HLA-E Antigens; C494688:GATA1 protein, human