The mechanical regulation of microRNA epitranscriptomics in heart failure

尽管在治疗和预防方面取得了进展，心力衰竭（HF）仍然是世界范围内发病率和死亡率的主要原因。心脏在机械力的作用下不断适应环境，这一过程被称为心脏重塑。过度的机械负荷是病理性心脏重构的主要驱动因素，逐渐导致心衰。一组microrna （miRs）对机械力（mechanomir）有反应，并参与心脏病理生理和心衰。表观转录组学（即RNA的生化修饰）正在成为影响编码和非编码RNA的基因表达调控的新层面。n6 -腺苷RNA甲基化（m6A）调节miR转录物（pri-miRs）向功能性miRs的加工，促进心肌梗死后血管生成和心脏修复。然而，据报道m6A的失调有助于HF的发生。表转录组学在心脏机械反应和mechanomiR调节中所起的作用尚未被研究，尽管它对变革性治疗至关重要。Epi-mecHEART旨在揭示导致心衰的机械诱导的表转录组机制，重点关注机械因子。结合“活体心肌切片”和计算技术（可在宿主实验室获得）与分子技术和生物力学工具，我将I)确定机械过载下心肌细胞的机械敏感性n6甲基化反应；ii)揭示机械过载如何调节pri-miRs和miR-mRNA靶点的n6甲基化谱；iii)研究机械诱导mrna的n6甲基化如何影响mir靶向功能iv)通过临床样本验证机械诱导的HF n6甲基化变化的临床相关性。靶向n6甲基化代表了一种变革性的策略，以支持心脏适应增加的工作量，从而预防心力衰竭。

Despite advances in therapies and prevention, heart failure (HF) remains a leading cause of morbidity and mortality worldwide. The heart is exposed to mechanical forces and constantly adapts to its environment in a process known as cardiac remodelling. Excessive mechanical load is a major driver of pathological cardiac remodelling, progressively leading to HF. A set of microRNAs (miRs) are responsive to mechanical forces (mechanomiRs) and contribute to heart pathophysiology and HF. Epitranscriptomics (i.e., the biochemical modification of the RNA) is emerging as a new layer of gene expression regulation affecting both coding and non-coding RNAs. N6-adenosine RNA methylation (m6A) regulate the processing of miR transcripts (pri-miRs) to functional miRs, promoting angiogenesis and cardiac repair after myocardial infarction. However, dysregulation of m6A reportedly contributes to HF. The role played by epitranscriptomics in heart mechanical responses and mechanomiR regulation have not yet been investigated, although crucial to inform transformative therapeutics. Epi-mecHEART aims to unveil the mechanically induced epitranscriptomic mechanisms leading to HF, focussing on mechanomiRs. Combining "living myocardial slice" and computational technologies (available at the host lab) with molecular techniques and biomechanical tools, I will i) identify the mechanosensitive N6-methylation responses in cardiomyocytes subjected to mechanical overload; ii) unveil how mechanical overload modulates the N6-methylation profile of both pri-miRs and miR-mRNA targets; iii) investigate how the mechanically induced N6-methylation on mRNAs impacts miR-targeting function iv) validate the clinical relevance of mechanically-induced N6-methylation changes in HF, by use of clinical samples. Targeting N6-methylation represents a transformative strategy to support the adaptation of the heart to increased workload, thus preventing HF.