FBR: Dr. Vicent Pelechano

Speaker: Dr. Vicent Pelechano
Professor of RNA Biology, Karolinska Institutet (Sweden); SciLifeLab Group Leader; Wallenberg Academy Fellow

Hidden layers of gene regulation: integrating RNA decay, translation and spatial biology

Abstract:
All cells share the same DNA, yet they behave very differently. Our team aims to uncover hidden layers of gene regulation underpinning this diversity by studying subtle differences in RNA dynamics. To achieve this, we develop innovative technologies to dissect mRNA life, bridging the discovery of fundamental mechanisms to clinical applications.

By studying mRNA decay, we have shown that co-translational mRNA degradation provides a unique window into ribosome dynamics and cellular adaptation. Using sequencing of 5′-phosphorylated mRNA degradation intermediates (5PSeq), we can map the in vivo position of the last translating ribosome, enabling high-resolution analyses of the coupling between translation and mRNA decay. We have recently shown that, under nutrient limitation, a large fraction of the transcriptome undergoes −1 ribosomal frameshifting. This process, conserved from bacteria to yeast and humans, can restrain cell growth under stress. Modulating this process may open new avenues to alleviate proteostasis defects and influence the production of neoantigens.

In bacteria, I will show how RNA degradome sequencing enables rapid, species-specific post-transcriptional profiling of microbial communities. This approach allows phenotypic antimicrobial resistance (AMR) to be assessed using molecular readouts of ribosome dynamics, distinguishing sensitive and resistant strains without relying on predefined marker genes.

Beyond RNA decay, I will show how integrating dynamic measurements of gene and protein expression in cancer cells enables the identification of transient cell states underlying phenotypic plasticity. These approaches can be used to detect plastic cell populations in leukaemia and other cancers, providing new avenues to understand and target tumour heterogeneity.

Finally, I will introduce scART, a novel technology we have developed to interrogate RNA regulation at subcellular and single-cell resolution. scART enables direct, multiplexed measurement of mRNA subcellular localisation together with ribosome association. I will demonstrate how scART reveals dynamic and condition-specific changes in mRNA localisation and translation that are not accessible with existing approaches. We anticipate that scART will substantially advance our understanding of cell-specific mRNA localisation, RNA-binding protein interactions, and translational regulatory heterogeneity.