FROM RNA REGULATION TO FAT LOSS

Obesity and obesity-associated diseases are global health challenges. Taking the advantage of a rapid and genetically tractable model organism, the nematode Caenorhabditis elegans, we uncovered a novel mechanism linking fat loss to mRNA regulation. Specifically, we identified a homeostatic rheostat, consisting of a conserved endoribonuclease, REGE-1, and its mRNA target encoding a fat loss-promoting transcription factor, ETS-4, whose expression promotes the loss of body fat. In contrast to well-studied transcriptional regulation of body fat, the post-transcriptional regulation remains a largely uncharted territory. Thus, on the one hand, we investigated the mechanism of mRNA degradation by REGE-1. On the other hand, we searched for ETS-4 target genes driving the fat loss. REGE-1 is homologous to the human MCPIP1/Zc3h12a/Regnase-1 degrading diverse mRNAs. There are two models of Regnase-1-mediated mRNA silencing. One model proposes that Regnase-1 functions with another RNA-binding protein, Roquin-1, which recruits Regnase-1 to specific mRNAs. The other model postulates that the two proteins function separately. Studying the ets-4 mRNA degradation by REGE-1, we have uncovered its functional relationship with RLE-1/Roquin-1. However, although both proteins are essential for ets-4 mRNA silencing, REGE-1 and RLE-1 appear to associate with mRNA independently of each other. Thus, although the functional interdependence between REGE-1/Regnase-1 and RLE-1/Roquin-1 is conserved, the mechanisms underlying their cooperation may vary between species. Intriguingly, although Regnase-1 is known to target many diverse transcripts, our analysis suggests that ets-4 mRNA may be the sole target of REGE-1. It suggests a model where REGE-1 controls various aspects of animal physiology by regulating the abundance of a single master regulator, ETS-4, which in turn controls the transcription of diverse effectors. In the context of body fat regulation, our findings suggest that ETS-4 may induce the fat loss by upregulating genes involved in sphingolipid metabolism. Future studies of orthologous proteins in other species could shed more light on the evolution of this exciting mRNA silencing mechanism, potentially revealing a prototypic silencing mechanism involving both proteins.

The project yielded novel insights into a conserved post-transcriptional mechanism regulating animal physiology with potential biomedical implications. The results were published in high-impact journals, strengthening our stance and visibility in the fields of RNA biology and animal physiology. International collaborations conducted in the timeframe of this project increased the know-how capital and technical competence of the laboratory and the department. The ongoing research resulting from the project is expected to fuel further discoveries, future cooperation, and joint grant applications.

Current medicinal treatments of obesity are suboptimal, due to detrimental neurological side effects as most drugs target appetite. Thus, there is an urgent need for new molecular targets for chemical interventions. Such targets can be identified through the exploration of novel fat-controlling mechanisms. We use the nematode Caenorhabditis elegans as a rapid genetic model to uncover such mechanisms. We have identified a homeostatic rheostat, consisting of a conserved endoribonuclease (RNase) and a fat loss-promoting transcription factor, whose reciprocal regulation determines the levels of body fat. In contrast to well-studied transcriptional regulation of body fat, the post-transcriptional regulation remains a largely uncharted territory. Thus, on the one hand, we will determine how exactly the RNase silences specific messenger RNAs. On the other hand, we will determine how precisely the transcription factor induces fat loss. Subsequently, the functional conservation of uncovered mechanisms will be examined in mammalian models of obesity, potentially opening a new avenue to the treatment of obesity