Expanded CUG repeat RNA alters gene expression profiles in myotonic dystrophy model cells

Myotonic dystrophy type 1 (DM1) is a dominantly inherited disorder due to a toxic gain of function of RNA transcripts containing expanded CUG repeats (CUGexp). Patients with DM1 present with multisystemic symptoms, such as muscle wasting, cognitive impairment, cataract, frontal baldness, and endocrine defects, which resemble accelerated aging. Although the involvement of cellular senescence, a critical component of aging, was suggested in studies of DM1 patient-derived cells, the detailed mechanism of cellular senescence caused by CUGexp RNA remains unelucidated. Here, we developed a DM1 cell model that conditionally expressed CUGexp RNA in human primary cells so that we could perform a detailed assessment that eliminated the variability in primary cells from different origins. To identify the pathway that induced cellular senescence, we conducted comprehensive gene expression analysis using RNA sequencing (RNA-Seq) in CUGexp+ and CUGexp- cells. Overall design: We analyzed of mRNA expression in CUGexp+ and CUGexp- cells.

1型强直性肌营养不良症（Myotonic dystrophy type 1, DM1）是一种显性遗传性疾病，其致病机制为携带扩增型CUG重复序列（CUGexp）的RNA转录本产生毒性功能获得效应。DM1患者会出现多系统临床表现，包括肌肉萎缩、认知障碍、白内障、前额秃发及内分泌缺陷，此类症状与衰老加速表型高度相似。尽管已有研究在DM1患者来源的细胞中提出细胞衰老（cellular senescence）——作为衰老进程的关键组分——参与了疾病发生，但由CUGexp RNA诱导细胞衰老的具体分子机制仍未阐明。本研究构建了可在人类原代细胞（primary cells）中条件性表达CUGexp RNA的DM1细胞模型，借此消除不同来源原代细胞的个体差异，从而开展精细化的机制评估。为了筛选诱导细胞衰老的信号通路，研究团队利用RNA测序（RNA sequencing, RNA-Seq）对CUGexp阳性与阴性细胞进行了全面的基因表达分析。实验整体设计：本研究分析了CUGexp阳性与阴性细胞的mRNA表达水平。