Institute of Pharmacology and Toxicology, Paracelsus Medical University, 5020, Salzburg, Austria.
Institute of Neurobiology, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovak Republic.
Mol Neurobiol. 2020 Feb;57(2):752-764. doi: 10.1007/s12035-019-01731-5. Epub 2019 Aug 30.
PPARGC1A encodes a transcriptional co-activator also termed peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1-alpha (PGC-1α) which orchestrates multiple transcriptional programs. We have recently identified CNS-specific transcripts that are initiated far upstream of the reference gene (RG) promoter. The regulation of these isoforms may be relevant, as experimental and genetic studies implicated the PPARGC1A locus in neurodegenerative diseases. We therefore studied cis- and trans-regulatory elements activating the CNS promoter in comparison to the RG promoter in human neuronal cell lines. A naturally occurring variable guanidine thymidine (GT) repeat polymorphism within a microsatellite region in the proximal CNS promoter increases promoter activity in neuronal cell lines. Both the RG and the CNS promoters are activated by ESRRA, and the PGC-1α isoforms co-activate ESRRA on their own promoters suggesting an autoregulatory feedback loop. The proximal CNS, but not the RG, promoter is induced by FOXA2 and co-activated by PGC-1α resulting in robust activation. Furthermore, the CNS, but not the RG, promoter is targeted by the canonical hypoxia response involving HIF1A. Importantly, the transactivation by HIF1A is modulated by the size of the GT polymorphism. Increased expression of CNS-specific transcripts in response to hypoxia was observed in an established rat model, while RG transcripts encoding the full-length reference protein were not increased. These results suggest a role of the CNS region of the PPARGC1A locus in ischemia and warrant further studies in humans as the activity of the CNS promoter as well as its induction by hypoxia is subject to inter-individual variability due to the GT polymorphism.
PPARGC1A 编码一种转录共激活因子，也称为过氧化物酶体增殖物激活受体 (PPAR)γ 共激活因子 1-α（PGC-1α），它协调多种转录程序。我们最近鉴定了起始于参考基因（RG）启动子上游很远的中枢神经系统特异性转录本。这些异构体的调节可能是相关的，因为实验和遗传研究将 PPARGC1A 基因座牵连到神经退行性疾病中。因此，我们研究了在人类神经元细胞系中与 RG 启动子相比，中枢神经系统启动子的顺式和反式调节元件。在中枢神经系统近端启动子中的微卫星区域内存在一个自然发生的可变鸟嘌呤胸腺嘧啶（GT）重复多态性，增加了神经元细胞系中的启动子活性。RG 和 CNS 启动子均被 ESRRA 激活，PGC-1α 异构体自身在其启动子上共激活 ESRRA，提示存在自反馈调节环。近端 CNS，但不是 RG，启动子被 FOXA2 诱导并与 PGC-1α 共激活导致强烈激活。此外，中枢神经系统，但不是 RG，启动子是由涉及 HIF1A 的经典缺氧反应靶向的。重要的是，HIF1A 的反式激活受 GT 多态性大小的调节。在建立的大鼠模型中观察到缺氧时中枢神经系统特异性转录本的表达增加，而编码全长参考蛋白的 RG 转录本没有增加。这些结果表明 PPARGC1A 基因座的中枢神经系统区域在缺血中起作用，并需要在人类中进一步研究，因为 CNS 启动子的活性及其对缺氧的诱导受到 GT 多态性的个体间变异性的影响。
