Arnaud Vanden Broeck, a researcher at the Centre d'Ingénierie des Protéines (CIP) at the University of Liège, has just been awarded a Starting Grant from the European Research Council to develop his TranSplice project. This fundamental research project aims to deepen our understanding of kinetoplastids, a family of unicellular eukaryotes responsible for serious tropical diseases and could lead to new treatments to combat the diseases they cause, which affect not only humans but also crops and livestock.
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inetoplastids are a family of flagellate protists that includes numerous parasitic species responsible for serious human diseases such as sleeping sickness, Chagas disease, and leishmaniasis. These unicellular eukaryotes have a unique cellular and molecular biology that differs from that of the majority of other organisms, making their study both fascinating and essential for combating the diseases they cause.
At the heart of the TranSplice fundamental research project, led by Arnaud Vanden Broeck, is the study of an essential yet little-understood molecular mechanism: SL trans-splicing. This process enables kinetoplastids to generate their messenger RNAs (mRNAs) from long polycistronic precursors by adding a small RNA molecule, the 'Spliced Leader' (SL), to the 5' end of each mRNA via a unique machinery called the trans-spliceosome.
"To explain it more simply, the genome of a cell, made up of DNA, is like a vast library containing all the instructions needed to produce proteins, which are essential to life and the proper functioning of the cell," explains Arnaud Vanden Broeck. In most organisms, each book in this library represents an instruction (a messenger RNA) for producing a single protein. These books are initially printed in draft form, containing clear (exons) and incomprehensible (introns) chapters. Before these books can be used to make proteins, the cell eliminates the incomprehensible chapters by a process called "splicing", then protects the instructions by adding a front and back cover, thus ensuring that they are correctly read and translated into proteins. In kinetoplastids, however, this process is quite different. The instructions for making proteins are grouped together in huge books (called polycistronic messenger RNAs), each containing the recipes for producing hundreds of proteins. Unlike other organisms, these large books do not have incomprehensible chapters, but they are too large to be used as they are. Before they can be used, the cell must cut them into smaller books, each containing just one recipe and a first cover (the SL RNA). This cutting and organising process, called SL trans-splicing, is complex and essential to kinetoplastids."
The TranSplice research project aims to unravel the mysteries of this particular mechanism. Using cutting-edge technologies such as genome editing using the CRISPR/Cas9 molecular scissors, high-resolution cryogenic electron microscopy and artificial intelligence, the researchers hope to understand how these parasites organise and use their genetic material. This understanding could pave the way for new treatments to eradicate the diseases caused by these parasites.
TranSplice promises to provide innovative tools for research in biology, parasitology, and medicine, and it could even have repercussions in biotechnology," adds the researcher. An in-depth study of the RNA trans-splicing mechanism could, for example, improve SMaRT technology, a gene therapy method that uses cellular splicing mechanisms to correct defective genes."
ULiège's TranSplice project represents a major research initiative that could ultimately transform the way we understand and combat some of the most persistent and dangerous tropical diseases. By deciphering how kinetoplastids work, Arnaud Vanden Broeck hopes not only to discover new strategies for combating these diseases but also to develop biotechnological tools that could transform research in biology and medicine.
Passionate about science since his earliest childhood, Arnaud Vanden Broeck holds a master's degree in Biochemistry, Molecular and Cellular Biology from the University of Liège obtained in 2014. He then undertook a PhD in Biophysics and Structural Biology at the Institut de Génétique, Biologie Moléculaire et Cellulaire (IGBMC) in Strasbourg, under the supervision of Dr Valérie Lamour. His thesis focused on the structural study of type 2 DNA topoisomerases, both bacterial and human, and on the mechanisms of inhibition of these enzymes by therapeutic compounds. In 2019, he continued his research and move to the United States to begin an EMBO-funded postdoctoral fellowship in Dr Sebastian Klinge's laboratory at New York's Rockefeller University. For five years, he focused his research on the structural elucidation of human ribosome assembly using cryogenic electron microscopy. Arnaud Vanden Broeck's work has been published in several leading international journals (Science, Nature Structural and Molecular Biology, Molecular Cell). He also won the Scaringe Prize awarded by the International RNA Society. In 2024, he was awarded an FNRS Research associate contract and an ERC Starting Grant to return to the University of Liège, where he set up his laboratory within the Centre for Protein Engineering (InBioS research unit/Faculty of Science) to continue his research into the regulation of gene expression in kinetoplastid parasites.
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