Neuroprotection by Heat Shock Factor-1 (HSF1) and Trimerization-Deficient Mutant Identifies Novel Alterations in Gene Expression.
Neuroprotection by Heat Shock Factor-1 (HSF1) and Trimerization-Deficient Mutant Identifies Novel Alterations in Gene Expression.
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DOI：
10.1038/s41598-018-35610-1
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发表时间：
2018-11-22
影响因子：
4.6
通讯作者：
D'Mello SR
中科院分区：
文献类型：
--
作者：
Qu Z;Titus ASCLS;Xuan Z;D'Mello SR
热休克因子-1(HSF1)通过刺激热休克蛋白(HSPs)编码基因的转录，保护神经元免于因错误折叠蛋白的积累而死亡。这种刺激作用依赖于三聚体HSF1与HSP基因启动子内序列的关联。然而，我们最近描述了HSF-AB，HSF1的一个突变形式，既不能同源三聚化，也不能与HSP基因启动子结合，也不能刺激HSP的表达，它对神经元的保护作用与野生型HSF1一样有效，这表明HSF1激活了另一种神经保护机制。为了深入了解HSF1和HSF1-AB保护神经元的机制，我们使用RNA-Seq技术确定了这些蛋白质在健康的小脑颗粒神经元(CGN)或准备死亡的神经元中诱导的转录变化。当HSF1在健康神经元中异位表达时，鉴定出1211个差异表达基因(DEG)，其中1075个上调。当HSF1在准备死亡的神经元中表达时，393个基因上调，32个基因下调。与之形成鲜明对比的是，HSF1-AB在正常神经元中改变了13个基因的表达，而在细胞凋亡条件下仅改变了6个基因的表达，提示HSF1-AB的神经保护作用可能是通过非转录机制介导的。我们通过定量聚合酶链式反应验证了15个基因的表达变化。虽然其他研究已经进行了RNA-Seq分析来识别HSF1靶点，但我们使用原代神经元进行的研究发现了一些可能在大脑维护和功能方面发挥特殊作用的新靶点。
Heat shock factor-1 (HSF1) protects neurons from death caused by the accumulation of misfolded proteins by stimulating the transcription of genes encoding heat shock proteins (HSPs). This stimulatory action depends on the association of trimeric HSF1 to sequences within HSP gene promoters. However, we recently described that HSF-AB, a mutant form of HSF1 that is incapable of either homo-trimerization, association with HSP gene promoters, or stimulation of HSP expression, protects neurons just as efficiently as wild-type HSF1 suggesting an alternative neuroprotective mechanism that is activated by HSF1. To gain insight into the mechanism by which HSF1 and HSF1-AB protect neurons, we used RNA-Seq technology to identify transcriptional alterations induced by these proteins in either healthy cerebellar granule neurons (CGNs) or neurons primed to die. When HSF1 was ectopically-expressed in healthy neurons, 1,211 differentially expressed genes (DEGs) were identified with 1,075 being upregulated. When HSF1 was expressed in neurons primed to die, 393 genes were upregulated and 32 genes were downregulated. In sharp contrast, HSF1-AB altered expression of 13 genes in healthy neurons and only 6 genes in neurons under apoptotic conditions, suggesting that the neuroprotective effect of HSF1-AB may be mediated by a non-transcriptional mechanism. We validated the altered expression of 15 genes by QPCR. Although other studies have conducted RNA-Seq analyses to identify HSF1 targets, our study performed using primary neurons has identified a number of novel targets that may play a special role in brain maintenance and function.
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影响因子：
3.3
作者：
Fujimoto M;Hayashida N;Katoh T;Oshima K;Shinkawa T;Prakasam R;Tan K;Inouye S;Takii R;Nakai A
通讯作者：
Nakai A
DOI：
10.1073/pnas.152330499
发表时间：
2002-12-10
影响因子：
11.1
作者：
Bonini, NM
通讯作者：
Bonini, NM
影响因子：
3.5
作者：
Evangelisti, C.;Bianco, F.;Bonora, E.
通讯作者：
Bonora, E.
影响因子：
4.8
作者：
Dai, RJ;Frejtag, W;Mivechi, NF
通讯作者：
Mivechi, NF
影响因子：
10.5
作者：
Conlon EG;Manley JL
通讯作者：
Manley JL