There is an increasing number of small RNA pathways that are intimately involved in the regulation of gene expression. These small RNA pathways are found to be critical for maintaining genome organisation and have also been shown to regulate the genome across generations through epigenetic mechanisms. In C. elegans a diverse repertoire of small RNA regulatory pathways operate in both the soma and germline that share similarities in biogenesis and mechanism of action, but diverge in targeting and regulatory role. The diverse functions of small RNA pathways include licensing of transcription and genome protection by limiting deleterious transcription or gene expression (genome protection from foreign elements). Aside from the core factors such as Argonaute’s and their mediating proteins (ALG/AIN), there exist a series of modulating co-factors. Usually the presence of certain so-called co-factors, in addition to the core factors, is pathway dependent for regulating the efficiency of either biogenesis, targeting or action of these small RNAs. One such co-factor defined in the miRNA pathway is the TRIM-NHL protein, NHL-2, which was studied for roles in miRISC activity of let-7 and lsy-6 targets in the soma.
We have identified that NHL-2 holds more functions than just within miRISC activity, of most significance is a fundamental role in germline functions and reproductive capacity. We show a clear requirement for nhl-2 in germline immortality and clear roles in transgenerational epigenetic inheritance. Further to the somatic and germline functions we show a role in the nuclear RNAi pathway, which makes nhl-2 a promiscuous gene in opposing (licensing and repressive chromatin marks) RNA regulatory pathways. This is supported through biochemical studies showing physical interactions with key Argonaute proteins and additionally through small RNA-seq data. Collectively, we show a promiscuous modulating co-factor that forms a hub of gene regulatory activity in both the germline and soma.