WEHI Wednesday Seminar hosted by Professor Aaron Jex
 

Dr Balu Balan
Research Officer – Jex Laboratory, Infection and Global Health division, WEHI
 

RNA-Binding Proteins: One of the Key Regulators of Cell Fate in Early Eukaryotes

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

Post-transcriptional regulation is the process by which cells manage RNAs after they’re made, utilising built-in cis-factors (RNA signals) and trans-factors, such as RNA-binding proteins (RBPs) or small RNAs, to control RNA processing, localisation, lifespan, and translation. RBPs guide how cells develop, differentiate and respond to stress. When RBPs malfunction, they contribute to neurodegenerative and muscle disorders as well as cancer, and infectious pathogens often hijack these RBPs to promote infection. Of the 63 protein families found in all life, 53 bind RNA. Unlike prokaryotes, which rely on a minimal RBP toolkit, eukaryotes expanded theirs to include dedicated factors for splicing, RNA transport, translational repression, RNA silencing and granule assembly. Every core human RBP role already exists in yeast, and studies in protist pathogens show these proteins steering cell fate and isoform diversity long before modern lineages evolved. Yet, despite their central biological and medical importance, we still lack a clear understanding of how the RBP toolkit first evolved. Did entirely new RBPs emerge right at the dawn of eukaryogenesis?

Our phylogenomic RBP atlas across the tree of life shows that RBPs are a unifying feature of molecular life, with the eukaryotic RBPome shaped by both bacterial and archaeal systems alongside the emergence and expansion of novel RBP families. To pinpoint when this sophistication first arose, we turned to the early-diverging eukaryote Giardia duodenalis, predating yeast by a billion years and among the first eukaryotes to undergo a true cell-differentiation stage, marking a critical cell-fate decision point, as a “model system” to demonstrate that RBPs for RNA splicing, RNA silencing, translation repression and cell-fate regulation had already emerged at the dawn of eukaryotic life. We mapped its RBPome via computational modelling, transcriptomics, proteomics and interactome capture, uncovering both canonical and non-canonical RBPs. Then, through functional genetics, RNA-network profiling and phase-separation assays, we demonstrated that Giardia RBPs already mediate translational repression, biological condensate formation and cell-fate decisions. Our findings suggest that the complex regulation of RBP arose at the dawn of eukaryotes, underpinning their emergence and subsequent diversification. Reconstructing RBPs at their origin provides a minimal molecular blueprint for gene control, revealing how their disruption leads to disease aetiologies and developmental disorders.

All welcome!