MicroRNAs: From Mechanism to Organism.

Philipp J Dexheimer,Luisa Cochella

doi:10.3389/fcell.2020.00409

Philipp J Dexheimer, Luisa Cochella

Open Access

https://doi.org/10.3389/fcell.2020.00409

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Abstract

MicroRNAs (miRNAs) are short, regulatory RNAs that act as post-transcriptional repressors of gene expression in diverse biological contexts. The emergence of small RNA-mediated gene silencing preceded the onset of multicellularity and was followed by a drastic expansion of the miRNA repertoire in conjunction with the evolution of complexity in the plant and animal kingdoms. Along this process, miRNAs became an essential feature of animal development, as no higher metazoan lineage tolerated loss of miRNAs or their associated protein machinery. In fact, ablation of the miRNA biogenesis machinery or the effector silencing factors results in severe embryogenesis defects in every animal studied. In this review, we summarize recent mechanistic insight into miRNA biogenesis and function, while emphasizing features that have enabled multicellular organisms to harness the potential of this broad class of repressors. We first discuss how different mechanisms of regulation of miRNA biogenesis are used, not only to generate spatio-temporal specificity of miRNA production within an animal, but also to achieve the necessary levels and dynamics of expression. We then explore how evolution of the mechanism for small RNA-mediated repression resulted in a diversity of silencing complexes that cause different molecular effects on their targets. Multicellular organisms have taken advantage of this variability in the outcome of miRNA-mediated repression, with differential use in particular cell types or even distinct subcellular compartments. Finally, we present an overview of how the animal miRNA repertoire has evolved and diversified, emphasizing the emergence of miRNA families and the biological implications of miRNA sequence diversification. Overall, focusing on selected animal models and through the lens of evolution, we highlight canonical mechanisms in miRNA biology and their variations, providing updated insight that will ultimately help us understand the contribution of miRNAs to the development and physiology of multicellular organisms.

Highlights

The Emergence of Small RNA-Guided Effector SystemsRegulation of gene expression by small RNAs emerged as an ancient feature of cellular biology and is found in all three domains of life
Having evolved primarily as a means of defense against foreign nucleic acids (Shabalina and Koonin, 2008; Obbard et al, 2009) the principle of small RNAs guiding effector proteins to selected nucleic acids via antisense-complementarity is a recurrent theme in biology
These RNA-based interference (RNAi) systems consist of two components, a nucleic acid allowing for sequence-specific target recognition, and an effector protein that mediates downstream effects with varying outcomes

Summary

Introduction

The Emergence of Small RNA-Guided Effector SystemsRegulation of gene expression by small RNAs emerged as an ancient feature of cellular biology and is found in all three domains of life (bacteria, archaea and eukarya). This is in part due to redundancy (Ge et al, 2012), most notably among miRNAs that fall into so-called families and share targeting specificity (Alvarez-Saavedra and Horvitz, 2010), and redundancy with other repressive mechanisms that contribute to the output of gene regulatory networks (acting either at the RNA or protein levels).

Results

Conclusion