Mechanosensitive M7G epitranscriptome in endothelial health and disease

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Project Summary RNA chemical modifications, collectively referred to as the “epitranscriptome”, have recently emerged as a novel layer of molecular control of gene expression. Most epitranscriptomic studies address N6- methyladenosine (m6A) of mRNA in human cancers. The molecular identity of endothelial mRNA epitranscriptome and its potential role in regulating vascular functions remains a major knowledge gap. Recent studies suggested that mammalian mRNAs are broadly chemically modified and mRNA modifications occur in a cell-type and cell-state dependent manner. N6-methyladenosine (m6A), the most abundant internal (outside of the 5’ cap) methylation in mammalian mRNA, has been linked to critical biological processes such as proliferation, development, and stem cell differentiation. Only few recent studies addressed the potential role of mRNA m6A in cardiomyocyte remodeling and endothelial activation. We recently discovered the presence of a new chemical modification, N7-methylguanosine (m7G) in mammalian mRNA. Systematic m7G mapping in endothelial mRNA and its potential role in vascular pathophysiology is an unexplored territory. Vascular endothelium is dynamically regulated by blood flow via mechano-transduction mechanisms. Endothelial activation by disturbed flow contributes to a wide range of vascular diseases. Atherosclerosis preferentially develops in arterial sites where endothelium is activated by local disturbed flow whereas unidirectional flow promotes endothelial health. Current atherosclerosis therapies mainly target systematic risk factors but not the vasculature per se. This underscores the significance and unique opportunity to identify and target novel mechanosensitive mechanisms in vascular endothelium. We have generated very strong data demonstrating that the mRNA m7G is dynamically regulated in endothelium by hemodynamics. Unidirectional flow (UF) markedly increases m7G but not m6A in endothelial mRNAs. Moreover, Methyltransferase-Like 7A (METTL7A) is a novel m7G writer governing the UF-induced mRNA m7G methylation in endothelium. The overall goal of this project is to delineate the novel molecular mechanisms by which mechano-sensitive METTL7A governs endothelial mRNA m7G and regulates vascular functions in vitro and in vivo. Moreover, we will devise innovative precision nanomedicine approaches targeting METTL7A-mediated pathways to treat atherosclerosis.