Muscleblind like splicing regulators (MBNLs) govern various RNA-processing steps, including alternative splicing, polyadenylation, RNA stability and mRNA intracellular localization. In myotonic dystrophy type 1 (DM1), the most common muscular dystrophy in adults, MBNLs are sequestered on toxic RNA containing expanded CUG repeats, which leads to disruption of MBNL-regulated processes and disease features of DM1. Herein, we show the significance of MBNLs in regulating microtranscriptome dynamics during the postnatal development of skeletal muscles and in microRNA (miRNA) misregulation observed in mouse models and patients with DM1. We identify multiple miRNAs sensitive to MBNL proteins insufficiency and reveal that many of them were postnatally regulated, which correlates with increases in the activity of these proteins during this process. In adult Mbnl1-knockout mice, miRNA expression exhibited an adult-to-newborn shift. We hypothesize that Mbnl1 deficiency influences miRNA levels through a combination of mechanisms. First, the absence of Mbnl1 protein results in alterations to the levels of pri-miRNAs. Second, MBNLs affect miRNA biogenesis by regulating the alternative splicing of miRNA primary transcripts. We propose that the expression of miR-23b, miR-27b and miR-24-1, produced from the same cluster, depends on the MBNL-sensitive inclusion of alternative exons containing miRNA sequences. Our findings suggest that MBNL sequestration in DM1 is partially responsible for altered miRNA activity. This study provides new insights into the biological roles and functions of MBNL proteins as regulators of miRNA expression in skeletal muscles.

中文翻译：

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MBNL 剪接因子调控骨骼肌的微转录组


肌盲样剪接调节因子 （MBNL） 控制各种 RNA 加工步骤，包括选择性剪接、聚腺苷酸化、RNA 稳定性和 mRNA 细胞内定位。在成人最常见的肌营养不良症 1 型 （DM1） 中，MBNL 被隔离在含有扩增 CUG 重复序列的有毒 RNA 上，这导致 MBNL 调节过程和 DM1 的疾病特征被破坏。在此，我们展示了 MBNLs 在骨骼肌出生后发育过程中调节微转录组动力学以及在小鼠模型和 DM1 患者中观察到的 microRNA （miRNA） 失调的重要性。我们鉴定了多个对 MBNL 蛋白不足敏感的 miRNA，并揭示了其中许多是出生后调节的，这与在此过程中这些蛋白质活性的增加相关。在成年 Mbnl1 敲除小鼠中，miRNA 表达表现出成人到新生儿的转变。我们假设 Mbnl1 缺陷通过多种机制的组合影响 miRNA 水平。首先，Mbnl1 蛋白的缺失导致 pri-miRNA 水平的改变。其次，MBNLs 通过调节 miRNA 初级转录本的选择性剪接来影响 miRNA 生物发生。我们提出，由同一簇产生的 miR-23b、miR-27b 和 miR-24-1 的表达取决于 MBNL 敏感包含含有 miRNA 序列的替代外显子。我们的研究结果表明，DM1 中的 MBNL 隔离是 miRNA 活性改变的部分原因。本研究为 MBNL 蛋白作为骨骼肌中 miRNA 表达调节因子的生物学作用和功能提供了新的见解。