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首页> 外文期刊>Molecular and Cellular Biology >Endoplasmic Reticulum Stress Induction of the Grp78/BiP Promoter: Activating Mechanisms Mediated by YY1 and Its Interactive Chromatin Modifiers
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Endoplasmic Reticulum Stress Induction of the Grp78/BiP Promoter: Activating Mechanisms Mediated by YY1 and Its Interactive Chromatin Modifiers

机译：Grp78 / BiP启动子的内质网应激诱导：YY1及其相互作用的染色质修饰剂介导的激活机制。

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The unfolded protein response is an evolutionarily conserved mechanism whereby cells respond to stress conditions that target the endoplasmic reticulum (ER). The transcriptional activation of the promoter of GRP78/BiP, a prosurvival ER chaperone, has been used extensively as an indicator of the onset of the UPR. YY1, a constitutively expressed multifunctional transcription factor, activates the Grp78 promoter only under ER stress conditions. Previously, in vivo footprinting analysis revealed that the YY1 binding site of the ER stress response element of the Grp78 promoter exhibits ER stress-induced changes in occupancy. Toward understanding the underlying mechanisms of these unique phenomena, we performed chromatin immunoprecipitation analyses, revealing that YY1 only occupies the Grp78 promoter upon ER stress and is mediated in part by the nuclear form of ATF6. We show that YY1 is an essential coactivator of ATF6 and uncover their specific interactive domains. Using small interfering RNA against YY1 and insertional mutation of the gene encoding ATF6α, we provide direct evidence that YY1 and ATF6 are required for optimal stress induction of Grp78. We also discovered enhancement of the ER-stressed induction of the Grp78 promoter through the interaction of YY1 with the arginine methyltransferase PRMT1 and evidence of its action through methylation of the arginine 3 residue on histone H4. Furthermore, we detected ER stress-induced binding of the histone acetyltransferase p300 to the Grp78 promoter and histone H4 acetylation. A model for the ER stress-mediated transcription factor binding and chromatin modifications at the Grp78 promoter leading to its activation is proposed.
机译：展开的蛋白质反应是一种进化上保守的机制，细胞可通过该机制对靶向内质网（ER）的应激条件作出反应。 GRP78 / BiP（一种存活的ER伴侣）的启动子的转录激活已被广泛用作UPR发作的指标。组成型表达的多功能转录因子YY1仅在内质网应激条件下激活Grp78启动子。以前，体内足迹分析表明，Grp78启动子的ER应激反应元件的YY1结合位点表现出ER应激诱导的占有率变化。为了理解这些独特现象的潜在机制，我们进行了染色质免疫沉淀分析，揭示了YY1仅在内质网应激时占据Grp78启动子，并且部分地由ATF6的核形式介导。我们显示YY1是ATF6的必不可少的激活因子，并揭示了它们的特定交互域。使用针对YY1的小分子干扰RNA和编码ATF6α的基因的插入突变，我们提供了直接的证据表明YY1和ATF6是Grp78最佳应激诱导所必需的。我们还发现通过YY1与精氨酸甲基转移酶PRMT1的相互作用增强了ER胁迫诱导的Grp78启动子，并通过组蛋白H4上的精氨酸3残基的甲基化作用证明了其作用。此外，我们检测到内质网应激诱导的组蛋白乙酰转移酶p300与Grp78启动子的结合和组蛋白H4乙酰化。提出了ER应激介导的转录因子结合和Grp78启动子导致其激活的染色质修饰的模型。

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