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首页> 外文期刊>Molecular and Cellular Biology >Histone Deacetylase Activity Represses Gamma Interferon-Inducible HLA-DR Gene Expression following the Establishment of a DNase I-Hypersensitive Chromatin Conformation
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Histone Deacetylase Activity Represses Gamma Interferon-Inducible HLA-DR Gene Expression following the Establishment of a DNase I-Hypersensitive Chromatin Conformation

机译：组蛋白脱乙酰酶活性抑制DNase I超敏感染色质构象建立后γ干扰素诱导的HLA-DR基因表达。

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Expression of the retinoblastoma tumor suppressor protein (Rb) is required for gamma interferon (IFN-γ)-inducible major histocompatibility complex class II gene expression and transcriptionally productive HLA-DRA promoter occupancy in several human tumor cell lines. Treatment of these Rb-defective tumor cell lines with histone deacetylase (HDAC) inhibitors rescued IFN-γ-inducible HLA-DRA and -DRB mRNA and cell surface protein expression, demonstrating repression of these genes by endogenous cellular HDAC activity. Additionally, Rb-defective, transcriptionally incompetent tumor cells retained the HLA-DRA promoter DNase I-hypersensitive site. Thus, HDAC-mediated repression of the HLA-DRA 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 HLA-DRA promoter activation by HDAC activity likely involves a YY1 binding element located in the first exon of the HLA-DRA gene. Chromatin immunoprecipitation experiments localized YY1 to the HLA-DRA gene in Rb-defective tumor cells. Additionally, mutation of the YY1 binding site prevented repression of the promoter by HDAC1 and partially prevented activation of the promoter by trichostatin A. Mutation of the octamer element also significantly reduced the ability of HDAC1 to confer repression of inducible HLA-DRA promoter activation. Treatment of Rb-defective tumor cells with HDAC inhibitors greatly reduced the DNA binding activity of Oct-1, a repressor of inducible HLA-DRA promoter activation. These findings represent the first evidence that HDAC activity can repress IFN-γ-inducible HLA class II gene expression and also demonstrate that HDAC activity can contribute to promoter repression following the establishment of a DNase I-hypersensitive chromatin conformation.
机译：γ干扰素（IFN-γ）诱导的主要组织相容性复合体II类基因表达和转录生产性HLA-DRA启动子在几种人类肿瘤细胞系中的表达需要视网膜母细胞瘤肿瘤抑制蛋白（Rb）的表达。用组蛋白脱乙酰基酶（HDAC）抑制剂处理这些Rb缺陷型肿瘤细胞系可拯救IFN-γ诱导的HLA-DRA和-DRB mRNA和细胞表面蛋白的表达，证明内源性细胞HDAC活性可抑制这些基因。此外，Rb缺陷，转录不适合的肿瘤细胞保留了HLA-DRA启动子DNase I的超敏位点。因此，HDAC-DRA启动子的HDAC介导的抑制发生在建立明显的无核小体的启动子区域之后，并在所需的反式激活子转录产生该启动子之前。通过HDAC活性抑制HLA-DRA启动子激活可能涉及位于HLA-DRA基因第一个外显子中的YY1结合元件。染色质免疫沉淀实验将YY1定位于Rb缺陷肿瘤细胞中的HLA-DRA基因。此外，YY1结合位点的突变阻止了HDAC1对启动子的抑制，而部分阻止了曲古抑菌素A对启动子的激活。八聚体元素的突变也显着降低了HDAC1赋予抑制诱导型HLA-DRA启动子激活的能力。用HDAC抑制剂处理Rb缺陷型肿瘤细胞大大降低了Oct-1的DNA结合活性，Oct-1是诱导型HLA-DRA启动子激活的阻遏物。这些发现代表了HDAC活性可以抑制IFN-γ诱导的HLA II类基因表达的第一个证据，并且还证明了HDAC活性可以在建立DNase I超敏感染色质构象后促进启动子的抑制。

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