
<ArticleTitle>Histone deacetylase activity represses <prot>gamma interferon</prot>-inducible <prot>HLA-DR</prot> gene expression following the establishment of a <prot>DNase I</prot>-hypersensitive chromatin conformation.</ArticleTitle>
<AbstractText>Expression of the <prot>retinoblastoma tumor suppressor protein</prot> (<prot>Rb</prot>) is required for <prot>gamma interferon</prot> (<prot>IFN-gamma</prot>)-inducible major histocompatibility complex class II gene expression and transcriptionally productive <prot>HLA-DRA</prot> promoter occupancy in several human tumor cell lines. Treatment of these <prot>Rb</prot>-defective tumor cell lines with histone deacetylase (<prot>HDAC</prot>) inhibitors rescued <prot>IFN-gamma</prot>-inducible <prot>HLA-DRA</prot> and -DRB mRNA and cell surface protein expression, demonstrating repression of these genes by endogenous cellular <prot>HDAC</prot> activity. Additionally, <prot>Rb</prot>-defective, transcriptionally incompetent tumor cells retained the <prot>HLA-DRA</prot> promoter <prot>DNase I</prot>-hypersensitive site. Thus, <prot>HDAC</prot>-mediated repression of the <prot>HLA-DRA</prot> promoter occurs following the establishment of an apparent nucleosome-free promoter region and before transcriptionally productive occupancy of the promoter by the required transactivators. Repression of <prot>HLA-DRA</prot> promoter activation by <prot>HDAC</prot> activity likely involves a <prot>YY1</prot> binding element located in the first exon of the <prot>HLA-DRA</prot> gene. Chromatin immunoprecipitation experiments localized <prot>YY1</prot> to the <prot>HLA-DRA</prot> gene in <prot>Rb</prot>-defective tumor cells. Additionally, mutation of the <prot>YY1</prot> binding site prevented repression of the promoter by <prot>HDAC1</prot> and partially prevented activation of the promoter by trichostatin A. Mutation of the octamer element also significantly reduced the ability of <prot>HDAC1</prot> to confer repression of inducible <prot>HLA-DRA</prot> promoter activation. Treatment of <prot>Rb</prot>-defective tumor cells with <prot>HDAC</prot> inhibitors greatly reduced the DNA binding activity of <prot>Oct-1</prot>, a repressor of inducible <prot>HLA-DRA</prot> promoter activation. These findings represent the first evidence that <prot>HDAC</prot> activity can repress <prot>IFN-gamma</prot>-inducible HLA class II gene expression and also demonstrate that <prot>HDAC</prot> activity can contribute to promoter repression following the establishment of a <prot>DNase I</prot>-hypersensitive chromatin conformation.</AbstractText>
