The complexities of microRNA regulation: mirandering around the rules

MicroRNAs (miRNAs) are an important class of non-coding small RNAs that possess a large range of biological activities in a variety of organisms and are linked to human diseases such as cancer. Initially, miRNAs were thought to act solely as negative regulators of gene expression and exert their effects by binding to regions within the 3′UTR of their target protein-coding messenger RNAs (mRNAs) in a sequence dependent manner. However, recent data reveals that miRNA regulation entails a far more complex system of post-transcriptional control than initially appreciated. An evolving consensus has emerged of how miRNAs can repress as well as activate gene expression by interacting with complementary regions found in the promoter, coding region, as well as the 3′UTR of their mRNA targets. Furthermore, miRNAs are extensively regulated at the levels of miRNA promoter transcription, methylation, miRNA processing, RNA editing, and miRNA–target interactions. This review will discuss new insights into miRNA-based mechanisms and the role specific DNA- and RNA-binding factors play in fine-tuning gene expression in both negative and positive ways by directing miRNA biogenesis and activity. We will also discuss the influence that cellular context and environmental cues have on miRNA function. In the future, a clear understanding of miRNA regulation will be essential when understanding the role miRNAs play during animal development and in maintaining adult homeostasis as well as exploring the use of small RNAs for diagnostic and therapeutic purposes.