Circadian rhythms are oscillating physiological and behavioral changes governed by an internal molecular clock, and dysfunctions in circadian rhythms have been associated with ageing and various neurodegenerative diseases. However, the evidence directly connecting the neurodegeneration-associated proteins to circadian control at the molecular level remains sparse. Using meta-analysis, synchronized animals and cell lines, cells and tissues from FUS R521C knock-in rats, we examined the role of FUS in circadian gene expression regulation. We found that FUS, an oscillating expressed nuclear protein implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), exerted a novel feedback route to regulate circadian gene expression. Nr1d1-encoded core circadian protein REV-ERBα bound the Fus promoter and regulated the expression of Fus. Meanwhile, FUS was in the same complex as PER/CRY, and repressed the expression of E box-containing core circadian genes, such as Per2, by mediating the promoter occupancy of PSF-HDAC1. Remarkably, a common pathogenic mutant FUS (R521C) showed increased binding to PSF, and caused decreased expression of Per2. Therefore, we have demonstrated FUS as a modulator of circadian gene expression, and provided novel mechanistic insights into the mutual influence between circadian control and neurodegeneration-associated proteins.

中文翻译：

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神经退行性变相关的 FUS 是一种新的昼夜节律基因表达调节因子

昼夜节律是由内部分子钟控制的振荡生理和行为变化，昼夜节律的功能障碍与衰老和各种神经退行性疾病有关。然而，在分子水平上直接将神经变性相关蛋白与昼夜节律控制联系起来的证据仍然很少。使用荟萃分析、同步动物和细胞系、来自 FUS R521C 敲入大鼠的细胞和组织，我们检查了 FUS 在昼夜节律基因表达调节中的作用。我们发现 FUS 是一种与肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 发病机制有关的振荡表达核蛋白，它发挥了一种新的反馈途径来调节昼夜节律基因的表达。Nr1d1 编码的核心昼夜节律蛋白 REV-ERBα 与 Fus 启动子结合并调节 Fus 的表达。同时，FUS 与 PER/CRY 处于同一复合物中，通过介导 PSF-HDAC1 的启动子占有率来抑制 Per2 等含有 E 盒的核心昼夜节律基因的表达。值得注意的是，一种常见的致病突变体 FUS (R521C) 显示出与 PSF 的结合增加，并导致 Per2 的表达减少。因此，我们已经证明 FUS 作为昼夜节律基因表达的调节剂，并为昼夜节律控制和神经退行性疾病相关蛋白之间的相互影响提供了新的机制见解。一种常见的致病突变体 FUS (R521C) 显示与 PSF 的结合增加，并导致 Per2 的表达减少。因此，我们已经证明 FUS 作为昼夜节律基因表达的调节剂，并为昼夜节律控制和神经退行性疾病相关蛋白之间的相互影响提供了新的机制见解。一种常见的致病突变体 FUS (R521C) 显示与 PSF 的结合增加，并导致 Per2 的表达减少。因此，我们已经证明 FUS 作为昼夜节律基因表达的调节剂，并为昼夜节律控制和神经退行性疾病相关蛋白之间的相互影响提供了新的机制见解。