"My vision for the UK DRI Centre at King’s is to enhance its interdisciplinary approaches, and capacity to take molecular insights towards the clinic through innovative gene therapy technologies." Jernej Ule
UK DRI Centre Director
Jernej Ule obtained his BSc in Molecular Biology from University of Ljubljana, Slovenia in 1999. He went on to complete a PhD and postdoctoral programme with Dr Robert Darnell at the Rockefeller University (New York) before starting his own research group at the MRC Laboratory of Molecular Biology (Cambridge) in July 2006. He then moved with his team to the Queen Square UCL Institute of Neurology (London), before taking up the position of Group Leader at the Francis Crick Institute which he has held since 2016. Since 2020, he also started a satellite team at the Institute of Chemistry in Ljubljana funded by ERC advanced grant. In April 2022, Prof Ule begins his leadership of the UK DRI at King’s as Centre Director, where he will move his team to start a programme of research investigating RNA biology in Amyotrophic lateral sclerosis and Frontotemporal dementia. He aims to maintain a small satellite team at the Crick until 2024.
1. At a glance
Amyotrophic lateral sclerosis (ALS), or motor neurone disease (MND), is a fatal condition that causes progressive weakness of the muscles due to the degeneration of motor neurones in the brain and spinal cord. Although there are some treatments available to slow progression, greater understanding of the underlying causes is needed to develop more effective treatments, and help those affected live longer, healthier lives.
Prof Jernej Ule’s research is focused on a versatile molecule called ribonucleic acid (RNA), which has many roles in cells. RNA interacts with proteins to form large complexes, and evidence suggests that changes in these interactions can lead to the characteristic toxic aggregates seen in neurodegenerative diseases like ALS and Frontotemporal dementia. By developing innovative new biochemical and computational techniques, Prof Ule’s team aims to find out why this occurs and how to stop it using new therapeutics.
2. Scientific goals
Ribonucleoprotein complexes (RNPs) form when proteins bind to an RNA molecule, helping guide the RNA on its journey through the cell, while the RNAs also regulate the functions of bound proteins. These complexes have many regulatory roles in development, but mutations in RNA-binding proteins (RBPs) or non-coding RNAs are thought to lead to condensation and aggregation of RNPs in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).
The underlying mechanism is linked to changes in the dynamics of RNP assembly and disassembly, driven by interactions mediated by intrinsically disordered regions (IDRs) of RBPs and the bound RNAs. Prof Jernej Ule’s lab has built a framework of experimental and computational methods to study the mechanisms that drive RNP condensation, and how this contributes to cellular transitions in development and disease. They develop techniques, including iCLIP (individual-nucleotide resolution UV crosslinking and immunoprecipitation of protein-RNA complexes), which integrate biochemistry and computational biology to obtain a comprehensive map of interactions between proteins and their RNA partners within cells.
Main objectives and research goals:
In his UK DRI research programme, Prof Ule aims to examine the fundamental principles guiding the assembly and dynamics of RNPs that play central roles in FTD/ALS. He will:
1. Use the team’s systems biology toolbox to study the impact of disease-causing mutations on RNP condensation and functions to identify approaches that could re-establish the appropriate RNP functions.
2. Develop new tools to modulate the assembly and dynamic properties of RNPs and to explore their therapeutic potential.
3. Team members
Dr Martina Hallegger (Postdoctoral Researcher)
Dr Tamara Hodgetts (Postdoctoral Researcher)
Dr Losub Ira (Postdoctoral Researcher)
Dr Cristina Militti (Postdoctoral Researcher)
Dr Flora Lee (Postdoctoral Researcher)
Dr Julian Zagalak (Postdoctoral Researcher)
Dr Rupert Faraway (Postdoctoral Researcher)
Dr Patrick Toolan-Kerr (Postdoctoral Researcher)
Dr Miha Modic (Postdoctoral Researcher)
Dr Joyita Mukherjee (Postdoctoral Researcher)
Dr Anob Chakrabarti (Postdoctoral Researcher)
Dr Rafiee Mahmoud-Reza (Postdoctoral Researcher)
Karen Davey (Research Assistant)
Holly Digby (Research Assistant)
Within UK DRI:
- Dr Marc-David Ruepp, UK DRI at King's
- Prof Chris Shaw, UK DRI at King's
- Dr Lorena Arancibia Carcamo, UK DRI at UCL & The Francis Crick Institute
- Prof Giampietro Schiavo, UK DRI at UCL
- Prof Adrian Isaacs, UK DRI at UCL
Beyond UK DRI:
- Prof Giovanna Mallucci, Altos Labs
- Prof Sonia Gandhi, The Francis Crick Institute
- Prof Rickie Patani, The Francis Crick Institute
- Prof Pietro Fratta, UCL ION
- Prof Nicholas L Fawzi, Brown University (USA)
- Prof James Shorter, University of Pennsylvania (USA)
- Prof Ben Blencowe, University of Toronto (Canada)
- Prof Sila Ultanir, The Francis Crick Institute
- Prof Eugene Makeyev, King's College London
- Prof Nicholas Luscombe, Okinawa Institute of Science and Technology (Japan)
Amyotrophic lateral sclerosis (ALS), ageing, protein-RNA networks, ribonucleoproteins (RNPs), RNP condensation, intrinsically disordered regions, RNA structure
iCLIP, Ribo-seq, hiCLIP, bioinformatics, machine learning, proximity-interactome studies, proteomics, advanced imaging, protein-RNA biochemistry, pluripotent cell culture and differentiation, CRISPR-Cas9, CRISPR-Cas13
7. Key publications
Hallegger M*, Chakrabarti AM, Lee FCY, Lee BL, Amalietti AG, Odeh HM, Copley KE, Rubien JD, Portz B, Kuret K, Huppertz I, Rau F, Patani R, Fawzi NL, Shorter J, Luscombe NM, Ule J.* (2021) TDP-43 condensation properties specify its RNA-binding and regulatory repertoire, Cell. 2021 Sep 2;184(18):4680-4696.e22.
Attig J*, Agostini F, Gooding C, Chakrabarti AM, Singh A, Haberman N, Zagalak JA, Emmett W, Smith CWJ, Luscombe NM, Ule J* (2018) Heteromeric RNP assembly at LINEs controls lineage-specific RNA processing, Cell, Aug 23;174(5):1067-1081.e17
Soreq L; UK Brain Expression Consortium; North American Brain Expression Consortium, Rose J, Soreq E, Hardy J, Trabzuni D, Cookson MR, Smith C, Ryten M, Patani R*, Ule J* (2017) Major shifts in glial regional identity are a transcriptional hallmark of human brain aging, Cell Reports, Jan 10;18(2):557-570
Sibley RC*, Emmett W*, Blazquez L, Faro A, Haberman N, Briese M, Trabzuni D, Ryten M, Hardy J, UK Brain Expression Consortium, Modic M, Curk T, Wilson SW, Plagnol V*, Ule J* (2015) Recursive splicing in long vertebrate genes. Nature, May 21;521(7552):371-5.
Sugimoto Y, Vigilante A, Darbo E, Zirra A, Militti C, D’Ambrogio A, Luscombe N*, Ule J* (2015) hiCLIP reveals the in vivo atlas of mRNA secondary structures recognized by Staufen 1. Nature, Mar 26;519(7544):491-4.
(* = co-corresponding authors)