Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany.
Institute of Human Genetics, University of Lübeck, 23538 Lübeck, Germany.
Int J Mol Sci. 2022 Feb 17;23(4):2231. doi: 10.3390/ijms23042231.
X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative disorder that manifests as adult-onset dystonia combined with parkinsonism. A SINE-VNTR-Alu (SVA) retrotransposon inserted in an intron of the gene reduces its expression and alters splicing in XDP patient-derived cells. As a consequence, increased levels of the intron retention transcript can be found in XDP cells as compared to healthy controls. Here, we investigate the sequence of the deep intronic region included in this transcript and show that it is also present in cells from healthy individuals, albeit in lower amounts than in XDP cells, and that it undergoes degradation by nonsense-mediated mRNA decay. Furthermore, we investigate epigenetic marks (e.g., DNA methylation and histone modifications) present in this intronic region and the spanning sequence. Finally, we show that the SVA evinces regulatory potential, as demonstrated by its ability to repress the promoter in vitro. Our results enable a better understanding of the disease mechanisms underlying XDP and transcriptional alterations caused by SVA retrotransposons.
X 连锁型肌张力障碍-帕金森病（XDP）是一种严重的神经退行性疾病，表现为成年起病的肌张力障碍合并帕金森病。一个插入 基因内含子中的短散在重复元件-可变数量串联重复（SINE-VNTR-Alu，SVA）反转录转座子会降低其表达并改变 XDP 患者来源细胞中的剪接。因此，与健康对照组相比，XDP 细胞中可以发现 内含子保留转录本的水平增加。在这里，我们研究了包含在该转录本中的深内含子区域的序列，并表明它也存在于来自健康个体的细胞中，尽管其丰度低于 XDP 细胞，并且它通过无意义介导的 mRNA 降解进行降解。此外，我们研究了该内含子区域和跨越序列中存在的表观遗传标记（例如，DNA 甲基化和组蛋白修饰）。最后，我们表明 SVA 具有调节潜能，这表现在其能够在体外抑制 启动子。我们的研究结果有助于更好地理解 XDP 的疾病机制以及 SVA 反转座子引起的转录改变。
