RNA Interference and Biophysical Modulation Are Two Independent Mechanisms of MicroRNAs
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Date
2023-05
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The Ohio State University
Abstract
MicroRNAs (miRs) are small non-coding RNA (~22 nucleotides in length) that are well conserved in plants and animals. It has been widely known that miRs regulate gene expression via the classical mRNA interference (RNAi) mechanism. In brief, miR is loaded into an Ago (Argonaute) family protein to form an RNA-induced silencing complex and directly binds to the 3' untranslated region (UTR) of mRNA with partially complementary sequences of the seed sequence (the 2nd to 8th nucleotides of miR), resulting in reduced translation and/or stability of the mRNA of targeted genes. Each miR has hundreds of directly-targeted genes and subsequently regulates thousands of genes. The classical RNAi mechanism is a powerful mechanism that miRs regulate all biological activities.
Our lab, in previous studies, revealed a novel action of miRs beyond the RNAi mechanism. miR-1 are a predominant miR in the heart and play a critical role in the regulation of cardiac development and physiology. We found that endogenous miR-1 directly binds to an inward rectifier potassium ion channel Kir2.1 membrane protein and physically suppresses the inward rectifier potassium current (IK1) leading to biophysical modulation of cardiac electrophysiology. Our studies suggest that miRs modulate the homeostasis of tissues/organs via two mechanisms: 1) conventional RNAi to regulate the expression of proteins, including ion channels, which requires hours to days to take effect, and 2) newly-discovered direct binding with ion channels that quickly (seconds to minutes) results in biophysical modulation.
From our previous studies we found that a core sequence (AAG AAG, the 10th – 15th nucleotide of miR1) of biophysical action is outside the seed sequence of RNAi mechanism. We identified that some single-nucleotide miR-1 mutants (Mus), such as MU-10U, MU-14G, or MU-15A, are RNAi-only mutants that specifically disrupt biophysical action of miR1 while maintaining the RNAi mechanism. Therefore, we hypothesize that the RNAi and biophysical modulation are two independent mechanisms. As we have discovered RNAi-only mutants of miR1; here, we specifically hypothesize that there are also biophysical-only mutants of miRs that specifically disrupt the RNAi mechanism while maintaining biophysical actions. The separation of two mechanisms in miR1 mutants will demonstrate that biophysical modulation and RNAi are completely independent two mechanisms.
Description
PCB Department- Award of Poster Presentation (Undergraduate Trainee)
Keywords
Biophysical Modulation, Cardiomyocytes, Cardiac Arrhythmias, MicroRNA, RNA Interference (RNAi), Regulation of gene expression