FTO-Dependent m6A Regulates Cardiac Function During Remodeling and Repair

Background: Despite its functional importance in various fundamental bioprocesses, the studies of N6-methyladenosine (m6A) in the heart are lacking.Methods: We performed methylated (m6A) RNA immunoprecipitation sequencing (MeRIP-seq) to map transcriptome-wide m6A in healthy and failing hearts.Results: Improving expression of FTO in failing mouse hearts attenuated the ischemia-induced increase in m6A and decrease in cardiac contractile function. This is carried out by the demethylation activity of FTO, which selectively demethylates cardiac contractile transcriptsConclusion: Collectively, our study demonstrates the functional importance of FTO-dependent cardiac m6A methylome in cardiac contraction during heart failure and provides a novel mechanistic insight into the therapeutic mechanisms of FTO.

研究背景：尽管N6-甲基腺嘌呤（N6-methyladenosine, m6A）在多种基础生物过程中具有重要的功能意义，但目前针对心脏中该修饰的相关研究仍较为匮乏。
研究方法：我们采用甲基化（m6A）RNA免疫沉淀测序（MeRIP-seq）技术，绘制了健康心脏与心力衰竭心脏的全转录组m6A修饰图谱。
研究结果：在衰竭的小鼠心脏中提升脂肪量和肥胖相关蛋白（FTO）的表达，可缓解缺血诱导的m6A水平升高以及心脏收缩功能的下降。该调控作用依赖于FTO的去甲基化活性，后者可选择性地对心脏收缩相关转录本进行去甲基化修饰。
研究结论：综上，本研究证实了依赖于FTO的心脏m6A修饰组在心力衰竭过程中对心脏收缩功能的重要调控作用，并为FTO的治疗作用机制提供了全新的理论见解。