Context-specific microRNA function in developmental complexity

Abstract

Since their discovery, microRNAs (miRNA) have been implicated in a vast array of biological processes in animals, from fundamental developmental functions including cellular proliferation and differentiation, to more complex and specialized roles such as long-term potentiation and synapse-specific modifications in neurons. This review recounts the history behind this paradigm shift, which has seen small non-coding RNA molecules coming to the forefront of molecular biology, and introduces their role in establishing developmental complexity in animals. The fundamental mechanisms of miRNA biogenesis and function are then considered, leading into a discussion of recent discoveries transforming our understanding of how these molecules regulate gene network behaviour throughout developmental and pathophysiological processes. The emerging complexity of this mechanism is also examined with respect to the influence of cellular context on miRNA function. This discussion highlights the absolute imperative for experimental designs to appreciate the significance of context-specific factors when determining what genes are regulated by a particular miRNA. Moreover, by establishing the timing, location, and mechanism of these regulatory events, we may ultimately understand the true biological function of a specific miRNA in a given cellular environment.

Ontogeny of small RNA in the regulation of mammalian brain development

“…The behaviour of cells undergoing these neurodevelopmental processes is governed by spatiotemporal changes in gene expression [3]. Translation and intracellular traffic of these transcripts is influenced by small non-coding miRNA that function as molecular guide sequences for ribonucleoprotein complexes involved in targeted mRNA degradation or translational repression (reviewed [4–7]). By regulating mRNAs post-transcriptional fate, miRNA subsequently play a significant role in organizing complex patterns of gene activity.…”

Widespread context dependency of microRNA-mediated regulation

“…This is a consequence of the low specificity of seed matches alone: There are several lines of evidence suggesting that additional factors such as target site location (Grimson et al 2007), additional base-pairing at the microRNA 39 end (Brennecke et al 2005), target site accessibility (Kertesz et al 2007), other RNA binding proteins (Jacobsen et al 2010), microRNA and mRNA copy numbers (BenMoshe et al 2012;Carroll et al 2013), differential isoform usage (Sandberg et al 2008;Boutet et al 2012), and additional unknown factors or interplay between any of these play important roles in distinguishing functional from nonfunctional target sites. Interestingly, several of these additional factors are not static but may change dynamically, providing context for target recognition: For instance, depending on which RNA binding proteins (RBPs) are expressed at what level in a given cell-type, RISC may or may not Ó 2014 Erhard et al This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml).…”

“…In contrast, dynamic microRNA expression determines a global context, i.e., if a microRNA is differentially expressed, all of its targets are affected. This important distinction is often neglected; and often, only the global context is considered (Carroll et al 2013).…”

Cupid: simultaneous reconstruction of microRNA-target and ceRNA networks

“…Dissecting miRNA regulation, however, has proven challenging because candidate miRNA binding sites are ubiquitous and their regulatory effects are context specific (Liu et al 2005;Lu et al 2005;Mukherji et al 2011). As a result, and despite their relatively low accuracy, computational prediction methods that incorporate context-specific data are preferred for screening for miRNA-target interactions in tumor contexts (Carroll et al 2013;Erhard et al 2014).…”