The mechanical regulation of microRNA epitranscriptomics in heart failure

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.