Changes in m6A RNA methylation contribute to heart failure progression by modulating translation
Changes in m6A RNA methylation contribute to heart failure progression by modulating translation
复制标题
DOI：
10.1002/ejhf.1672
复制
发表时间：
2019-12-17
影响因子：
18.2
通讯作者：
Toischer, Karl
中科院分区：
文献类型：
--
作者：
Berulava, Tea;Buchholz, Eric;Toischer, Karl
目的 表观遗传过程的失调和基因表达异常是心力衰竭的重要机制。在这里，我们研究了 m6A RNA 甲基化在心力衰竭发展中的潜在相关性。方法和结果我们通过新一代测序分析了 m6A RNA 甲基化。我们发现健康小鼠和人类心脏中大约四分之一的转录本表现出 m6A RNA 甲基化。在进展为心力衰竭的过程中，我们观察到小鼠和人类 m6A RNA 甲基化的变化超过了基因表达的变化。 m6A RNA甲基化改变的RNA主要与代谢和调控途径有关，而RNA表达水平的变化主要代表结构可塑性的变化。从机制上讲，我们可以将 m6A RNA 甲基化与 RNA 翻译和蛋白质生产的改变联系起来。有趣的是，差异甲基化但不差异表达的RNA表现出差异的多核糖体占据，表明翻译的转录依赖性调节。此外，与对照小鼠相比，心肌细胞限制性敲除 RNA 去甲基酶 Fto 的小鼠表现出心脏功能受损。结论 我们可以证明 m6A 景观在心脏肥大和心力衰竭中发生改变。 m6A RNA 甲基化变化导致蛋白质丰度变化，与 mRNA 水平无关。这揭示了一种新的独立于转录的翻译调控机制。因此，我们的数据表明，m6A 甲基化等表观转录组过程的调节可能是治疗干预的一个有趣的目标。
Aims Deregulation of epigenetic processes and aberrant gene expression are important mechanisms in heart failure. Here we studied the potential relevance of m6A RNA methylation in heart failure development. Methods and results We analysed m6A RNA methylation via next-generation sequencing. We found that approximately one quarter of the transcripts in the healthy mouse and human heart exhibit m6A RNA methylation. During progression to heart failure we observed that changes in m6A RNA methylation exceed changes in gene expression both in mouse and human. RNAs with altered m6A RNA methylation were mainly linked to metabolic and regulatory pathways, while changes in RNA expression level mainly represented changes in structural plasticity. Mechanistically, we could link m6A RNA methylation to altered RNA translation and protein production. Interestingly, differentially methylated but not differentially expressed RNAs showed differential polysomal occupancy, indicating transcription-independent modulation of translation. Furthermore, mice with a cardiomyocyte restricted knockout of the RNA demethylase Fto exhibited an impaired cardiac function compared to control mice. Conclusions We could show that m6A landscape is altered in heart hypertrophy and heart failure. m6A RNA methylation changes lead to changes in protein abundance, unconnected to mRNA levels. This uncovers a new transcription-independent mechanisms of translation regulation. Therefore, our data suggest that modulation of epitranscriptomic processes such as m6A methylation might be an interesting target for therapeutic interventions.