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A GATA Factor Mediates Cell Type-Restricted Induction of HLA-E Gene Transcription by Gamma Interferon

By David M. Barrett, Karen S. Gustafson, Jing Wang, Shou Zhen Wang and Gordon D. Ginder

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-γ) induction of HLA-E gene transcription is mediated through a distinct IFN-γ-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-γ-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-γ 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-γ 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-γ 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-γ response from HLA-E promoter constructs containing a wild-type but not a GATA-1 mutant UIRR sequence and increased the IFN-γ response of the endogenous HLA-E gene. Knockdown of GATA-1 expression in K562 cells resulted in a ∼4-fold decrease in the IFN-γ response of the endogenous HLA-E gene, consistent with loss of the increase in IFN-γ 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-γ-mediated enhancement through the UIRR, but only partially reduced induction through the IRR, implicating p300/CBP binding to Stat-1α 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-γ induction of the HLA-E gene

Topics: Transcriptional Regulation
Publisher: American Society for Microbiology
Year: 2004
DOI identifier: 10.1128/MCB.24.14.6194-6204.2004
OAI identifier: oai:pubmedcentral.nih.gov:434230
Provided by: PubMed Central
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