Microguards and micromessengers of the genome

Abstract

The regulation of gene expression is of fundamental importance to maintain organismal function and integrity and requires a multifaceted and highly ordered sequence of events. The cyclic nature of gene expression is known as 'transcription dynamics'. Disruption or perturbation of these dynamics can result in significant fitness costs arising from genome instability, accelerated ageing and disease. We review recent research that supports the idea that an important new role for small RNAs, particularly microRNAs (miRNAs), is in protecting the genome against short-term transcriptional fluctuations, in a process we term 'microguarding'. An additional emerging role for miRNAs is as 'micromessengers'-through alteration of gene expression in target cells to which they are trafficked within microvesicles. We describe the scant but emerging evidence that miRNAs can be moved between different cells, individuals and even species, to exert biologically significant responses. With these two new roles, miRNAs have the potential to protect against deleterious gene expression variation from perturbation and to themselves perturb the expression of genes in target cells. These interactions between cells will frequently be subject to conflicts of interest when they occur between unrelated cells that lack a coincidence of fitness interests. Hence, there is the potential for miRNAs to represent both a means to resolve conflicts of interest, as well as instigate them. We conclude by exploring this conflict hypothesis, by describing some of the initial evidence consistent with it and proposing new ideas for future research into this exciting topic.

Figure 1

Eukaryotic RNA nomenclature and function. The small RNA family: small RNAs were initially defined as non-coding RNA molecules of 50–250 nucleotides (nt). However, with the discovery of a plethora of 19–32 nt non-coding families of RNAs over the last two decades, the term is now generally used to describe these ‘smaller' small non-coding RNAs (Perkel, 2013).

Figure 2

Biogenesis and mode of action of miRNAs. Pri-miRNA genes are transcribed from the genome by RNA polymerase II. The initial transcript is processed to become a shorter pre-miRNA by the microprocessor complex, a protein assembly of an RNase III enzyme known as Drosha and its RNA-binding partner, DGCR8 (also known as Pasha in fruit flies and worms). Exportin-5 facilitates the transport of the pre-miRNA into the cytoplasm. Here, the pre-miRNA undergoes further processing by an RNase III/helicase enzyme, Dicer, to become a ~22 bp miRNA duplex. The mature single-stranded miRNA is loaded into the RISC, which uses the miRNA sequence as a guide to bind complementary targets. Gene expression is modified by inhibition of ribosome loading, prevention of eukaryotic initiation factor function and mRNA cleavage.

Figure 3

An example scheme for microguarding, using the fruit fly example. Sex peptide (SP), one of ~130 male seminal fluid proteins, is transferred into the female during mating and activates the SP receptor in the female genital tract and central nervous system. The activated SP receptor initiates intracellular signalling that alters the transcription of genes involved in behaviour, embryology, immunity and ageing. In this hypothetical model, deleterious fluctuations of mRNA expression in the female (red), facilitated by receipt of male ejaculate proteins, are potentially smoothed and dampened by synchronous expression of miRNAs by females (green) as a potential defence mechanism to reduce costs.

Figure 4

A hypothetical model for miRNA transfer between the sexes. Here, miR-279, which is implicated in microguarding against the costs of gene expression variation in females arising from sexual conflict (Fricke et al., 2014), has the potential to be transferred to females from males during mating. miR-279 is expressed in the secondary cells of the D. melanogaster male accessory gland (Green et al., unpublished data). The inset shows a confocal micrograph of the tip of an accessory gland of a 1 day-old male reproductive system, in a transgenic line in which the expression of miR-279 is tagged to a GFP reporter (miR-279-GAL4; UAS-GFP; Cayirlioglu et al., 2008). The bi-nucleate arrangement of the nuclei in the accessory gland main cells is evident by DAPI staining (blue). Scale bar, 50 μM. These secondary cells can detach and transfer across to females during mating (Leiblich et al., 2012). The secondary cells also release microvesicles (MVs) that are similarly transferred during mating and that can interact with female tissues and alter female post mating receptivity (Corrigan et al., 2014). This system therefore offers a potential model for miRNA trafficking between the sexes, in a process likely to be shaped by sexual conflict.