Braun Maya, Shoshani Shachar, Tabach Yuval
Tabach Laboratory, Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University of Jerusalem, Jerusalem, Israel.
Front Mol Biosci. 2022 Aug 19;9:955753. doi: 10.3389/fmolb.2022.955753. eCollection 2022.
Myotonic dystrophy type 1 (DM1) is a multisystemic disease caused by pathogenic expansions of CTG repeats. The expanded repeats are transcribed to long RNA and induce cellular toxicity. Recent studies suggest that the CUG repeats are processed by the RNA interference (RNAi) pathway to generate small interfering repeated RNA (siRNA). However, the effects of the CTG repeat-derived siRNAs remain unclear. We hypothesize that the RNAi machinery in DM1 patients generates distinct gene expression patterns that determine the disease phenotype in the individual patient. The abundance of genes with complementary repeats that are targeted by siRNAs in each tissue determines the way that the tissue is affected in DM1. We integrated and analyzed published transcriptome data from muscle, heart, and brain biopsies of DM1 patients, and revealed shared, characteristic changes that correlated with disease phenotype. These signatures are overrepresented by genes and transcription factors bearing endogenous CTG/CAG repeats and are governed by aberrant activity of the RNAi machinery, miRNAs, and a specific gain-of-function of the CTG repeats. Computational analysis of the DM1 transcriptome enhances our understanding of the complex pathophysiology of the disease and may reveal a path for cure.
1型强直性肌营养不良症（DM1）是一种由CTG重复序列致病性扩增引起的多系统疾病。扩增的重复序列转录成长链RNA并诱导细胞毒性。最近的研究表明，CUG重复序列通过RNA干扰（RNAi）途径进行加工，以产生小干扰重复RNA（siRNA）。然而，CTG重复序列衍生的siRNA的作用仍不清楚。我们假设DM1患者体内的RNAi机制会产生独特的基因表达模式，这些模式决定了个体患者的疾病表型。每个组织中被siRNA靶向的具有互补重复序列的基因丰度决定了DM1中该组织受影响的方式。我们整合并分析了已发表的DM1患者肌肉、心脏和脑活检组织的转录组数据，揭示了与疾病表型相关的共同特征性变化。这些特征在带有内源性CTG/CAG重复序列的基因和转录因子中过度表达，并受RNAi机制、微小RNA（miRNA）的异常活性以及CTG重复序列的特定功能获得的调控。对DM1转录组的计算分析加深了我们对该疾病复杂病理生理学的理解，并可能揭示治愈途径。
