Schuy Jakob, Eisfeldt Jesper, Pettersson Maria, Shahrokhshahi Niloofar, Moslem Mohsen, Nilsson Daniel, Dahl Niklas, Shahsavani Mansoureh, Falk Anna, Lindstrand Anna
Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Front Genet. 2022 Feb 4;12:803683. doi: 10.3389/fgene.2021.803683. eCollection 2021.
Induced pluripotent stem cells (iPSCs) from patients are an attractive disease model to study tissues with poor accessibility such as the brain. Using this approach, we and others have shown that trisomy 21 results in genome-wide transcriptional dysregulations. The effects of loss of genes on chromosome 21 is much less characterized. Here, we use patient-derived neural cells from an individual with neurodevelopmental delay and a ring chromosome 21 with two deletions spanning 3.8 Mb at the terminal end of 21q22.3, containing 60 protein-coding genes. To investigate the molecular perturbations of the partial monosomy on neural cells, we established patient-derived iPSCs from fibroblasts retaining the ring chromosome 21, and we then induced iPSCs into neuroepithelial stem cells. RNA-Seq analysis of NESCs with the ring chromosome revealed downregulation of 18 genes within the deleted region together with global transcriptomic dysregulations when compared to euploid NESCs. Since the deletions on chromosome 21 represent a genetic "contrary" to trisomy of the corresponding region, we further compared the dysregulated transcriptomic profile in with that of two NESC lines with trisomy 21. The analysis revealed opposed expression changes for 23 genes on chromosome 21 as well as 149 non-chromosome 21 genes. Taken together, our results bring insights into the effects on the global and chromosome 21 specific gene expression from a partial monosomy of chromosome 21qter during early neuronal differentiation.
来自患者的诱导多能干细胞（iPSC）是一种极具吸引力的疾病模型，可用于研究诸如大脑等难以获取的组织。通过这种方法，我们和其他研究人员已表明，21三体综合征会导致全基因组转录失调。21号染色体上基因缺失的影响则鲜为人知。在此，我们使用了来自一名患有神经发育迟缓且带有环状21号染色体的个体的患者源性神经细胞，该环状染色体在21q22.3末端有两个跨度为3.8 Mb的缺失，包含60个蛋白质编码基因。为了研究部分单体性对神经细胞的分子扰动，我们从保留环状21号染色体的成纤维细胞中建立了患者源性iPSC，然后将iPSC诱导分化为神经上皮干细胞。对带有环状染色体的神经上皮干细胞进行RNA测序分析发现，与整倍体神经上皮干细胞相比，缺失区域内18个基因表达下调，同时还存在整体转录组失调。由于21号染色体上的缺失代表了与相应区域三体性相反的遗传状态，我们进一步将转录组失调谱与两个21三体综合征的神经上皮干细胞系进行了比较。分析发现，21号染色体上23个基因以及149个非21号染色体基因存在相反的表达变化。综上所述，我们的研究结果为21号染色体长臂末端部分单体性在早期神经元分化过程中对整体和21号染色体特异性基因表达的影响提供了见解。
