Inside the cell nucleus, the human genome is folded into a complex three-dimensional landscape. We have detailed maps of chromosomes, genes and regulatory elements, yet we still know little about how distant genes located on different chromosomes communicate to coordinate their activity. As an analogy, our world map does not indicate most natural corridors or man-made infrastructure that connect countries to one another. Worse, we barely understand how such connections function.
Recent discoveries have revealed many non-coding RNAs that act as structural molecules, helping to organise the genome. TRANS-3 challenges the traditional divide between “coding” and “non-coding” RNAs, asking whether even messenger RNAs (mRNA)—normally viewed only as transient templates for protein production—might also play non-coding structural roles while still in the nucleus.
The project is based on the hypothesis that mRNA molecules can shape genome architecture by forming “mRNA factories”: transient, membraneless condensates where genes that need to work together cluster in physical proximity to coordinate mRNA transcription and processing (e.g. splicing). By combining stem-cell models, live imaging, functional genomics, and physiological assays, TRANS-3 explores how these RNA factories assemble, function, and influence cell behaviour.
To make this concept experimentally tractable, the project uses the cardiac protein RBM20 as a paradigm. This RNA-binding factor and its target mRNAs form a factory that controls the splicing of key genes for heart contraction. Mutations in RBM20 cause severe forms of inherited cardiomyopathy, providing a disease-relevant model to study how disruption of nuclear organisation can lead to pathology. The project then examines whether similar mechanisms are pervasive for other mRNA factories, assessing how general the RBM20 paradigm may be across cell types and conditions.
The broader vision of TRANS-3 is to provide a new framework linking mRNA biology, nuclear structure, and human disease. Many conditions involve mutations in DNA- or RNA-binding proteins that may act as factory organisers; the same mechanism could also explain how genetic variants can unexpectedly influence the activity of genes located on other chromosomes—phenomena known as long-distance or trans-acting effects, which remain largely mysterious. By uncovering these hidden genomic “corridors,” TRANS-3 seeks to illuminate a fundamental yet unexplored layer of cellular regulation.
