Periodic Reporting for period 4 - MODVASC (Endothelial RNA Modifications in Vascular Homeostasis and Disease)
Reporting period: 2021-09-01 to 2023-02-28
RNA modifications are (non)/reversible, enzymatic ribonucleic acid (RNA) base modifications that expand the RNA alphabet from the 4 canonical nucleotides to more than 174 (a brief overview of RNA modifications is available here: http://modomics.genesilico.pl/modifications/). Importantly, they occur intrinsically in all of our cells. Among the most frequent RNA modifications are two different chemical processes both happening on a specific RNA nucleotide, adenosine, and they are termed deamination and methylation. My and other laboratories have reported that RNA modifications control all aspects of RNA life and are thus involved in several cellular processes and functions. The adenosine deamination to inosine is a process called RNA editing and is catalyzed by tasked enzymes, the adenosine deaminases acting on RNAs (ADARs). My laboratory has shown that adenosine deamination regulates cathepsin S mRNA stability by controlling the recruitment of the stabilizing RNA-binding protein called HuR onto the cathepsin S mRNA. Interestingly, we revealed a strong association of this RNA modification with vascular disease, documenting, for the first time, the importance of RNA modifications in cardiovascular system pathology. Adenosine methylation in the N6 position (m6A) is the most prominent RNA modification in eukaryotes and is catalyzed by a set of enzymes acting by being scavenged in another protein hub. This set of enzymes are termed METTL3, METT14 and WTAP. M6A RNA methylation is a highly conserved RNA modification among organisms and its presence in our cells has been shown to be essential for life. Accumulating recent evidence suggests that m6A RNA methylation controls cellular processes by interfering with the RNA – protein interaction and, thus, RNA fate.
Identifying the dynamically methylated RNAs of our cells and characterizing how m6A mediates a precise adjustment of RNA life to environmental stimuli will undoubtedly contribute towards the understanding of human disease. This may open the road to the development of new disease biomarkers and therapeutic strategies. MODVASC aims to explore the role of m6A RNA methylation in vascular endothelial cell function and in vascular disease. Specifically, MODVASC will characterize: a) the endothelial methylome, b) the regulatory effects of m6A RNA methylation in endothelial gene expression, c) the role of m6A RNA methylation machinery in vascular development and maintenance of vascular function and d) the regulation of m6A RNA methylation in vascular disease.
1) the in vivo implications of m6A RNA methylation-associated vascular endothelial homeostasis using the new genetic model we generated.
2) the elucidation of potentially common regulatory pathways controlling endothelial cell homeostasis and disease by using the established transcriptome-wide technologies.
3) the clinical value of m6A RNA methylation in atherosclerotic cardiovascular disease as well as inflammatory vascular diseases.