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Functional Analysis of the Transcription Repressor PLU-1/JARID1B

机译：转录阻遏物PLU-1 / JARID1B的功能分析

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The PLU-1/JARID1B nuclear protein, which is upregulated in breast cancers, belongs to the ARID family of DNA binding proteins and has strong transcriptional repression activity. To identify the target genes regulated by PLU-1/JARID1B, we overexpressed or silenced the human PLU-1/JARID1B gene in human mammary epithelial cells by using adenovirus and RNA interference systems, respectively, and then applied microarray analysis to identify candidate genes. A total of 100 genes showed inversely correlated differential expression in the two systems. Most of the candidate genes were downregulated by the overexpression of PLU-1/JARID1B, including the MT genes, the tumor suppressor gene BRCA1, and genes involved in the regulation of the M phase of the mitotic cell cycle. Chromatin immunoprecipitation assays confirmed that the metallothionein 1H (MT1H), -1F, and -1X genes are direct transcriptional targets of PLU-1/JARID1B in vivo. Furthermore, the level of trimethyl H3K4 of the MT1H promoter was increased following silencing of PLU-1/JARID1B. Both the PLU-1/JARID1B protein and the ARID domain selectively bound CG-rich DNA. The GCACA/C motif, which is abundant in metallothionein promoters, was identified as a consensus binding sequence of the PLU-1/JARID1B ARID domain. As expected from the microarray data, cells overexpressing PLU-1/JARID1B have an impaired G2/M checkpoint. Our study provides insight into the molecular function of the breast cancer-associated transcriptional repressor PLU-1/JARID1B.
机译：在乳腺癌中上调的PLU-1 / JARID1B核蛋白属于DNA结合蛋白的ARID家族，并具有很强的转录抑制活性。为了鉴定受PLU-1 / JARID1B调控的靶基因，我们分别通过使用腺病毒和RNA干扰系统在人乳腺上皮细胞中过表达或沉默人 PLU-1 / JARID1B 基因，然后应用微阵列分析以鉴定候选基因。在这两个系统中，共有100个基因显示出差异相关的反向表达。 PLU-1 / JARID1B的过表达下调了大多数候选基因，包括MT基因，抑癌基因 BRCA1 和参与有丝分裂细胞周期M期调控的基因。染色质免疫沉淀试验证实金属硫蛋白 1H （ MT1H ），- 1F 和- 1X 基因是直接转录的体内PLU-1 / JARID1B的靶标。此外，PLU-1 / JARID1B沉默后， MT1H 启动子的三甲基H3K4水平升高。 PLU-1 / JARID1B蛋白和ARID结构域均选择性结合富含CG的DNA。在金属硫蛋白启动子中丰富的GCACA / C基序被确定为PLU-1 / JARID1B ARID域的共有结合序列。从微阵列数据可以预期，过表达PLU-1 / JARID1B的细胞的G 2 / M检查点受损。我们的研究提供了乳腺癌相关的转录阻遏物PLU-1 / JARID1B的分子功能的见解。

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