Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
Nucleic Acids Res. 2020 Dec 16;48(22):12943-12956. doi: 10.1093/nar/gkaa1151.
Long noncoding (lnc)RNAs potently regulate gene expression programs in physiology and disease. Here, we describe a key function for lncRNA OIP5-AS1 in myogenesis, the process whereby myoblasts differentiate into myotubes during muscle development and muscle regeneration after injury. In human myoblasts, OIP5-AS1 levels increased robustly early in myogenesis, and its loss attenuated myogenic differentiation and potently reduced the levels of the myogenic transcription factor MEF2C. This effect relied upon the partial complementarity of OIP5-AS1 with MEF2C mRNA and the presence of HuR, an RNA-binding protein (RBP) with affinity for both transcripts. Remarkably, HuR binding to MEF2C mRNA, which stabilized MEF2C mRNA and increased MEF2C abundance, was lost after OIP5-AS1 silencing, suggesting that OIP5-AS1 might serve as a scaffold to enhance HuR binding to MEF2C mRNA, in turn increasing MEF2C production. These results highlight a mechanism whereby a lncRNA promotes myogenesis by enhancing the interaction of an RBP and a myogenic mRNA.
长链非编码 (lnc)RNA 能够在生理和疾病过程中有力地调节基因表达程序。在这里，我们描述了 lncRNA OIP5-AS1 在肌发生中的关键功能，肌发生是指成肌细胞在肌肉发育过程中分化为肌管，以及损伤后肌肉再生的过程。在人类成肌细胞中，OIP5-AS1 的水平在肌发生早期显著增加，其缺失减弱了肌生成分化，并强烈降低了肌生成转录因子 MEF2C 的水平。这种效应依赖于 OIP5-AS1 与 MEF2C mRNA 的部分互补性，以及 HuR 的存在，HuR 是一种与这两个转录本都有亲和力的 RNA 结合蛋白 (RBP)。值得注意的是，OIP5-AS1 沉默后，HuR 与 MEF2C mRNA 的结合丢失，这稳定了 MEF2C mRNA 并增加了 MEF2C 的丰度，这表明 OIP5-AS1 可能作为一个支架，增强 HuR 与 MEF2C mRNA 的结合，从而增加 MEF2C 的产生。这些结果强调了一种机制，即长链非编码 RNA 通过增强 RBP 和肌生成 mRNA 的相互作用来促进肌发生。
