Non-canonical features of microRNAs: paradigms emerging from cardiovascular disease

In this Review, Santovito and Weber discuss the functional relevance of non-canonical features of microRNAs for cardiovascular homeostasis and pathophysiology, describing the role of atypical microRNA biogenesis and localization, RISC heterogeneity, and non-conventional regulatory functions, including direct protein interactions and transcriptional regulation in the nucleus and in mitochondria.Research showing that microRNAs (miRNAs) are versatile regulators of gene expression has instigated tremendous interest in cardiovascular research. The overwhelming majority of studies are predicated on the dogmatic notion that miRNAs regulate the expression of specific target mRNAs by inhibiting mRNA translation or promoting mRNA decay in the RNA-induced silencing complex (RISC). These efforts mostly identified and dissected contributions of multiple regulatory networks of miRNA-target mRNAs to cardiovascular pathogenesis. However, evidence from studies in the past decade indicates that miRNAs also operate beyond this canonical paradigm, featuring non-conventional regulatory functions and cellular localizations that have a pathophysiological role in cardiovascular disease. In this Review, we highlight the functional relevance of atypical miRNA biogenesis and localization as well as RISC heterogeneity. Moreover, we delineate remarkable non-canonical examples of miRNA functionality, including direct interactions with proteins beyond the Argonaute family and their role in transcriptional regulation in the nucleus and in mitochondria. We scrutinize the relevance of non-conventional biogenesis and non-canonical functions of miRNAs in cardiovascular homeostasis and pathology, and contextualize how uncovering these non-conventional properties can expand the scope of translational research in the cardiovascular field and beyond