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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Grip1 -associated Set-domain Methyltransferase In Glucocorticoid Receptor Target Gene Expression
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Grip1 -associated Set-domain Methyltransferase In Glucocorticoid Receptor Target Gene Expression

机译：Grip1相关设置域甲基转移酶在糖皮质激素受体靶基因的表达。

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摘要

Transcriptional regulators such as the glucocorticoid receptor (GR) recruit multiple cofactors to activate or repress transcription. Although most cofactors are intrinsically bifunctional, little is known about the molecular mechanisms dictating the specific polarity of regulation. Furthermore, chromatin modifications thought to be confined to silent loci appear in actively transcribed genes suggesting that similar enzymatic activities may mediate constitutive and transient chromatin states. GRIP1, a GR ligand-dependent coregulator of the p160 family can potentiate or inhibit transcription but the molecular contexts and mechanisms that enable GRIP1 corepressor activity are poorly understood. In a yeast 2-hybrid screen with GRIP1 repression domain (RD)-containing fragment, we repeatedly isolated the C-terminal region of a SET domain-containing protein subsequently identified as histone H4 lysine 20 trimethyltransferase, Suv4-20h1. We cloned a full-length Suv4-20h1 and dissected its interaction with GRIP1 in yeast, in vitro, and in mammalian cells. Strict nuclear localization and high salt concentration required for Suv4-20h1 extraction were consistent with its tight association with chromatin. Overexpression of Suv4-20h1 in human U2OS and A549 cells expressing integrated and endogenous GR, respectively, antagonized ligand-dependent induction of a subset of GR target genes, whereas Suv4-20h1 siRNA-mediated depletion had a reciprocal effect. Inhibition of GR transactivation required both the GRIP1 interacting region of Suv4-20h1 and its catalytic activity. Thus, Suv4-20h1 known exclusively as a factor involved in constitutive heterochromatin maintenance, actively participates in hormone-dependent transcriptional regulation affecting GR target gene expression in a promoter- and cell type-specific manner.
机译：转录调节因子（例如糖皮质激素受体（GR））募集多种辅因子来激活或抑制转录。尽管大多数辅助因子本质上是双功能的，但对于指示特定调控极性的分子机制知之甚少。此外，被认为仅限于沉默基因座的染色质修饰出现在活跃转录的基因中，表明相似的酶活性可能介导了染色质的组成型和瞬时状态。 GRIP1是p160家族依赖GR配体的核心调节剂，可增强或抑制转录，但人们对GRIP1核心抑制剂活性的分子背景和机制了解甚少。在含有GRIP1阻遏域（RD）片段的酵母2杂交筛选中，我们反复分离了含有SET域的蛋白质的C端区域，随后将其鉴定为组蛋白H4赖氨酸20三甲基转移酶Suv4-20h1。我们克隆了全长的Suv4-20h1，并在酵母，体外和哺乳动物细胞中解剖了其与GRIP1的相互作用。 Suv4-20h1提取所需的严格核定位和高盐浓度与其与染色质的紧密结合是一致的。 Suv4-20h1在分别表达整合和内源GR的人U2OS和A549细胞中的过表达，拮抗了一部分GR目标基因的配体依赖性诱导，而Suv4-20h1 siRNA介导的耗竭则具有相互影响。抑制GR反式激活需要Suv4-20h1的GRIP1相互作用区域及其催化活性。因此，专门被称为组成型异染色质维持因子的Suv4-20h1以启动子和细胞类型特异性方式积极参与影响GR靶基因表达的激素依赖性转录调控。

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