m6A修饰介导环状RNA-circCDYL编码蛋白参与调控心肌肥大的机制研究

circular RNAs are new types of RNA played critical roles in disease, while their functions and mechanisms in cardiac hypertrophy are still not well understood. We found there is a circular transcript of CDYL gene, which named circCDYL, being significantly induced in cardiac hypertrophy and promoting cardiomyocyte hypertrophy. It was detected that circCDYL was associated with ribosomes, suggesting the protein-coding potential of circCDYL. We also observed that circCDYL has conserved ORF, the ORF can be translated into a truncated isoform of CDYL (tCDYL). Moreover, we noticed that circCDYL was m6A modificated, while m6A could regulate translation of circular RNA and involved in cardiac hypertrophy. Therefore, we suggested that m6A might induce circCDYL to encode tCDYL, which might promote cardiac hypertrophy. Therefore, the aim of this project is to study the function and molecular mechanism of circCDYL in cardiac hypertrophy: Whether circCDYL regulated cardiac hypertrophy by encoding truncated CDYL? Whether this process was induced by m6A modification? Our study will demonstrate the mechanism of m6A-circCDYL-tCDYL pathway in cardiac hypertrophy and serve a potential therapeutic avenue for cardiac hypertrophy.

环状RNA是一种在疾病中发挥重要调节功能的新型RNA，然而其在心肌肥大中的作用机理仍有待探究。我们的前期工作发现环状RNA-circCDYL在心肌肥大过程中表达量显著上升，能促进心肌细胞肥大。相关数据显示circCDYL可与核糖体结合，而且其序列中具有ORF，该ORF可编码一段截短的CDYL蛋白（tCDYL）。我们还注意到circCDYL有较高的m6A修饰水平，而m6A可调节环状RNA翻译蛋白，同时m6A水平升高又会促进心肌肥大。因此我们推测m6A修饰可介导circCDYL编码蛋白tCDYL，介由tCDYL促进心肌肥大。本项目拟在细胞和动物水平探明circCDYL在心肌肥大过程中的功能，明确其是否具有蛋白编码能力、其功能发挥是否受m6A修饰的调控。研究结果将阐明m6A-circCDYL-tCDYL信号通路在心肌肥大中所发挥的作用，为心肌肥大的治疗和药物开发提供新的靶点。

环状RNA是一种在疾病中发挥重要调节功能的新型RNA，然而其在心肌肥大中的作用机理仍有待探究。本项目发现心肌肥大的发展与环状RNA-circCDYL在心肌细胞中的表达上调相关。过表达circCDYL可造成心肌细胞肥大，而敲低circCDYL则抑制Ang II诱导的心肌细胞肥大。机制方面，circCDYL可作为模板编码一段截短的CDYL蛋白（tCDYL）。tCDYL可通过与CDYL竞争性结合REST，抵消CDYL的转录抑制功能，促进心肌肥大相关基因的表达，导致心肌肥大。CircCDYL的翻译受m6A修饰调控，心肌细胞肥大过程中circCDYL的m6A修饰水平上升，促进tCDYL的翻译。本项目揭示了环形RNA调控心肌肥大的新机制，对心肌肥大的治疗提供了理论依据和靶点。