Abstract
Highly precise, yet flexible and responsive coordination of expression across groups of genes underpins the integrity of many vital functions. However, our understanding of gene regulatory networks (GRNs) is often hampered by the lack of experimentally tractable systems, by significant computational challenges derived from the large number of genes involved or from difficulties in the accurate identification and characterization of gene interactions. Here we used a tractable experimental system in which to study GRNs: the genes encoding the seminal fluid proteins that are transferred along with sperm (the ‘transferome’) in Drosophila melanogaster fruit flies. The products of transferome genes are core determinants of reproductive success and, to date, only transcription factors have been implicated in the modulation of their expression. Hence, as yet, we know nothing about the post-transcriptional mechanisms underlying the tight, responsive and precise regulation of this important gene set. We investigated this omission in the current study. We first used bioinformatics to identify potential regulatory motifs that linked the transferome genes in a putative interaction network. This predicted the presence of putative microRNA (miRNA) ‘hubs’. We then tested this prediction, that post-transcriptional regulation is important for the control of transferome genes, by knocking down miRNA expression in adult males. This abolished the ability of males to respond adaptively to the threat of sexual competition, indicating a regulatory role for miRNAs in the regulation of transferome function. Further bioinformatics analysis then identified candidate miRNAs as putative regulatory hubs and evidence for variation in the strength of miRNA regulation across the transferome gene set. The results revealed regulatory mechanisms that can underpin robust, precise and flexible regulation of multiple fitness-related genes. They also help to explain how males can adaptively modulate ejaculate composition.
Highlights
Genes rarely, if ever, function in isolation from one another
We first evaluated the over-representation of miRNA target sites among the 30 untranslated region (UTR) of the transferome genes, when compared to the entire set of D. melanogaster 30 UTRs
The results showed evidence for the presence of regulatory miRNAs that modulate the expression of seminal fluid transferome genes in D. melanogaster, and more broadly, that cross referencing of regulatory regions to existing databases and unbiased methods for detecting regulation of unknown origin can successfully reveal signatures of gene regulation
Summary
If ever, function in isolation from one another. They are often interconnected within gene regulatory networks (GRNs) that regulate a specific pathway or function. A practical hurdle can be the difficulty in identifying an appropriate set of genes in which to study features of GRNs, both at the level of gene expression and the resulting phenotype. To facilitate the understanding of such a system, it should ideally: (i) comprise a tightly linked network of genes, (ii) represent a set of genes within a defined biological process and/or localized expression, (iii) be genetically tractable for experimental testing, and (iv) produce a well-defined and measureable phenotype. The set of genes that encode the non-sperm components of the ejaculate in male Drosophila melanogaster fruit flies [22] (hereafter the ‘transferome’ genes) fulfils these criteria They represent a potentially valuable exemplar because they: (i) show coordinated expression [23 –25], (ii) have defined functions and measureable phenotypes [26], and (iii) can be subjected to controlled, experimental genetic manipulations. Isotopic 15 N labelling has defined a set of extracellular proteins secreted by the male accessory glands, ejaculatory ducts and bulb, plus non-sperm molecules from the testes that represent the transferome and that are transferred to females during mating [22]
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