Qiu Jia-Jun, Liu Yan-Na, Ren Zhao-Rui, Yan Jing-Bin
Shanghai Children's Hospital, Shanghai Institute of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, China.
Shanghai Children's Hospital, Shanghai Institute of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, China; Key Laboratory of Embryo Molecular Biology, Ministry of Health of China and Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai 200040, China.
Int J Biochem Cell Biol. 2017 Nov;92:115-120. doi: 10.1016/j.biocel.2017.09.017. Epub 2017 Sep 29.
Trisomy 21 is the most common chromosomal disorder and underlies Down syndrome. Epigenetics, such as DNA methylation and post-translational histone modifications, plays a vital role in Down syndrome. However, the functions of epigenetics-related long noncoding RNAs (lncRNAs), found to have an impact on neural diseases such as Alzheimer's disease, remain unknown in Down syndrome. In this study, we analyzed the RNA sequencing data from Down syndrome-induced pluripotent stem cells (iPSCs) and normal iPSCs. A large number of lncRNAs were identified differentially expressed in Down syndrome-iPSCs. Notably, stronger perturbation was shown in the expression of lncRNAs compared to protein coding genes (Kolmogorov-Smirnov test, P<0.05), suggesting that lncRNAs play more important roles in Down syndrome. Through gene set enrichment analysis and bi-clustering, we also found that most of the differential expressed lncRNAs were closely associated with mitochondrial functions (e.g. mitochondrion organization, P=3.21×10; mitochondrial ATP synthesis coupled electron transport, P=1.73×10 and mitochondrial membrane organization, P=4.04×10). PCR-array and qRT-PCR results revealed that almost all genes related to mitochondria were down-regulated in Down syndrome-iPSCs, implying that mitochondria were dysfunctional in Down syndrome (e.g. ATP5B, Fold Change=-8.2317; COX6A1, Fold Change=-12.7788 and SLC25A17, Fold Change=-22.1296). All in all, our study indicated that a stronger perturbation of lncRNAs expression may lead to the dysfunction of mitochondria in Down syndrome.
21三体综合征是最常见的染色体疾病，是唐氏综合征的病因。表观遗传学，如DNA甲基化和翻译后组蛋白修饰，在唐氏综合征中起着至关重要的作用。然而，在唐氏综合征中，与表观遗传学相关的长链非编码RNA（lncRNA）的功能仍不清楚，已知这些lncRNA会对阿尔茨海默病等神经疾病产生影响。在本研究中，我们分析了唐氏综合征诱导多能干细胞（iPSC）和正常iPSC的RNA测序数据。在唐氏综合征-iPSC中鉴定出大量差异表达的lncRNA。值得注意的是，与蛋白质编码基因相比，lncRNA的表达受到更强的干扰（Kolmogorov-Smirnov检验，P<0.05），这表明lncRNA在唐氏综合征中发挥着更重要的作用。通过基因集富集分析和双聚类，我们还发现大多数差异表达的lncRNA与线粒体功能密切相关（例如线粒体组织，P=3.21×10；线粒体ATP合成偶联电子传递，P=1.73×10；线粒体膜组织，P=4.04×10）。PCR阵列和qRT-PCR结果显示，唐氏综合征-iPSC中几乎所有与线粒体相关的基因均下调，这意味着唐氏综合征中线粒体功能失调（例如ATP5B，倍数变化=-8.2317；COX6A1，倍数变化=-12.7788；SLC25A17，倍数变化=-22.1296）。总之，我们的研究表明，lncRNA表达的更强干扰可能导致唐氏综合征中线粒体功能障碍。
